Antiphospholipid Syndrome and Kidney Damage: Symptoms

Symptoms of antiphospholipid syndrome differ significantly in variety. The polymorphism of symptoms is determined by the localization of thrombi in the veins, arteries or small intragonal vessels. As a rule, thromboses recur either in the venous or in the arterial bed. The combination of thrombotic occlusion of peripheral vessels and vessels of the microcirculatory bed forms a clinical picture of multi-organ ischemia leading to multiple organ dysfunction in some patients.

The spectrum of arterial and venous thromboses and the clinical manifestations of antiphospholipid syndrome caused by them

Localization	Symptoms
Brain vessels	Relapses of acute cerebrovascular disorders, transient ischemic attacks, convulsive syndrome, chorea, migraine, dementia, Guillain-Barre syndrome, venous sinus thrombosis
Vessels of the eye	Thrombosis of the arteries and veins of the retina, atrophy of the optic nerve, blindness
Arteries of the spinal cord	Transverse myelitis
Coronary and intramyocardial vessels, valvular heart valves	Myocardial infarction, thrombotic microangiopathy of intramyocardial vessels with the development of myocardial ischemia, heart failure, arrhythmia; thrombosis of the shunt after coronary artery bypass grafting; endocarditis of Liebman-Saks; Valvular defects (usually mitral valve insufficiency)
Vessels of the lungs	Relapses of pulmonary embolism (small branches); pulmonary hypertension; hemorrhagic alveolitis
Liver vessels	Ischemic infarcts of the liver; Badda-Chiari syndrome
Kidneys	Renal vein thrombosis, renal artery thrombosis, kidney infarction, thrombotic microangiopathy
Vessels of the adrenal glands	Acute adrenal insufficiency, Addison's disease
Skin vessels	Reticulated liver, ulcers, palpable purpura, infarcts of the nail bed, digital gangrene
Aorta and peripheral arteries	Syndrome of the arch of the aorta; intermittent claudication, gangrene, aseptic necrosis of femur head
Peripheral veins	Thrombosis, thrombophlebitis, postphlebitic syndrome
Vessels of the placenta	Fetal loss syndrome (recurrent spontaneous abortions, antenatal fetal death, premature birth, high frequency of preeclampsia) due to thrombosis and infarction of the placenta

[1], [2], [3]

Renal damage

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 the lesion, its extent and the rate of development of the thrombo-occlusive process, the clinical picture may vary from acute renal failure with severe, sometimes malignant, arterial hypertension or without it to minimal urinary syndrome, mild or moderate hypertension, and a slowly progressive impairment of renal function.

Variants of kidney damage with antiphospholipid syndrome

Localization of thrombosis	Symptoms
Renal Vein The trunk of the renal artery (occlusion or stenosis) The branches of the renal artery Intraladial arteries, arterioles, glomerulus capillaries	Acute kidney failure, hematuria Renovascular hypertension, acute renal failure Kidney infarction, renovascular hypertension Thrombotic microangiopathy

Thrombosis of renal veins

Thrombosis of the renal veins is not a frequent manifestation of antiphospholipid syndrome. Perhaps both isolated development of renal vein thrombosis in situ, and the spread of thrombotic process from the inferior vena cava. In the latter case, bilateral lesions are more often noted. The clinical picture for thrombosis of the renal veins depends on the duration and severity of venous occlusion, as well as from one-sided or two-sided localization of the process. A sudden complete occlusion of one renal vein quite often proceeds asymptomatically. Clinically manifested thrombosis of the renal veins is manifested by pains of different intensity in the lumbar region and lateral abdomen, which is associated with overgrowth of the renal capsule, macrogemuria, the appearance of proteinuria and in some cases, sudden unexplained deterioration of renal functions. The last symptom is more typical for a bilateral thrombotic process. Until now, the diagnosis of thrombosis of the renal veins causes certain difficulties, given the frequent asymptomatic course.

Thrombosis or stenosis of the renal arteries

The defeat of the renal arteries in the antiphospholipid syndrome is represented by their complete occlusion as a result of thrombus formation in situ or thromboembolism by fragments of thrombotic overlap from the affected valves, as well as stenosis due to the organization of thrombi with recanalization or without it, and the development of fibrotic changes in the vascular wall. The main clinical symptom of vasocclusive affection of the renal arteries is renovascular arterial hypertension, the severity of which depends on the rate of development of occlusion, its severity (complete, incomplete) and localization (unilateral, bilateral). These same factors cause the possibility of developing acute renal failure, in a number of cases, combined with renovascular hypertension. Severe oliguric acute renal failure is especially characteristic for bilateral thrombosis of the renal arteries. In the latter case, with complete occlusion of the lumen of the vessel, it is possible to develop bilateral cortical necrosis with irreversible renal dysfunction. In the chronic course of the vasocclusive process and incomplete occlusion, renovascular arterial hypertension with varying degrees of chronic renal insufficiency is noted. Currently, renal artery disease associated with antiphospholipid syndrome has been considered as another cause of renal vascular hypertension along with atherosclerosis, vasculitis and fibromuscular dysplasia. In young patients with severe arterial hypertension, antiphospholipid syndrome with renal artery disease should be included in the range of diagnostic search.

The defeat of small intracranial vessels (APS-associated nephropathy)

Despite the importance of thrombosis of the renal arteries and veins, their development is noted in patients with antiphospholipid syndrome less often than the lesion of small intracranial vessels, which is based on thrombotic microangiopathy (see "Thrombotic microangiopathy").

Clinico-morphological manifestations and features of the pathogenesis of thrombotic microangiopathy within the antiphospholipid syndrome are similar to those in other microangiopathic syndromes, especially in HUS and TTP. Thrombotic microangiopathy of the intrarenal vessels in systemic lupus erythematosus has been described by P. Klemperer et al. In 1941, long before the notion of an antiphospholipid syndrome was formed, and since the beginning of the 1980s, thromboses of glomerular capillaries and intracranial arterioles in lupus nephritis have been associated with circulating lupus anticoagulant or an elevated titer of ACL. Renal thrombotic microangiopathy in patients with primary antiphospholipid syndrome was first described by P. Kincaid-Smith et al. In 1988. Observing in the dynamics of morphological changes in the kidneys in 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 a primary antiphospholipid syndrome, in which the morphological features of the peculiar vascular kidney damage characteristic of the antiphospholipid syndrome were analyzed, and the term "nephropathy associated with the antiphospholipid syndrome" was proposed for its name. The true incidence of nephropathy associated with the antiphospholipid syndrome has not been accurately established, however, according to preliminary data, it is 25% for the primary antiphospholipid syndrome and 32% for the secondary 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 with antiphospholipid syndrome

Symptoms of kidney damage associated with antiphospholipid syndrome are poorly expressed and often recede into the background in comparison with severe vasocclusive lesions of other organs (CNS, heart, lungs) that are noted in patients with primary antiphospholipid syndrome, which leads to untimely diagnosis of nephropathy. On the other hand, with systemic lupus erythematosus, the symptoms of nephropathy associated with the antiphospholipid syndrome may be masked by more vivid signs of lupus nephritis, which has long been considered the only dominant form of renal pathology. In connection with this, nephropathy associated with antiphospholipid syndrome is often not taken into account when choosing therapeutic tactics and estimating the prognosis for both primary and secondary antiphospholipid syndrome.

• The most common symptom of kidney damage with APS-AG, noted in 70-90% of patients with primary antiphospholipid syndrome. Most of them have moderate arterial hypertension, in some cases transient, although it is possible to develop malignant hypertension with damage to the brain and eyes, the development of irreversible acute renal failure. This type of flow is described mainly in the catastrophic antiphospholipid syndrome. The main pathogenetic mechanism of arterial hypertension in nephropathy associated with antiphospholipid syndrome is the activation of RAAS in response to renal ischemia, and at later stages also decrease their function. Evidence of the dominant role of kidney ischemia in the pathogenesis of hypertension is the detection of hyperplasia of the renin-containing cells of the juxtaglomerular apparatus with semi-open kidney biopsy or autopsy. In some patients, arterial hypertension may be the only symptom of kidney damage, but in most cases, it is identified with a combination of signs of impaired renal function.
• A feature of nephropathy associated with antiphospholipid syndrome is an early isolated decrease in GFR, which sometimes leads to a long-term disruption of the renal nitrogen function. Renal insufficiency, as a rule, is expressed moderately and has a slowly progressing course. Progression of chronic renal failure is more often associated with arterial hypertension. Irreversible acute renal failure, which develops in patients with a catastrophic antiphospholipid syndrome, is described only in combination with malignant arterial hypertension.
• Urinary syndrome is present in most patients with moderate isolated proteinuria. The development of nephrotic syndrome is possible and does not exclude the diagnosis of nephropathy associated with antiphospholipid syndrome. As a rule, growing proteinuria is noted with severe, poorly corrected arterial hypertension. Hematuria is not a common sign of nephropathy associated with antiphospholipid syndrome: it develops in less than 50% of patients in combination with proteinuria. Isolated microhematuria or macrohematuria are not described.

Perhaps acute and chronic course of nephropathy associated with antiphospholipid syndrome, with primary antiphospholipid syndrome.

• In acute course, the formation of an acute cold syndrome characterized by pronounced microhematuria and proteinuria in combination with arterial hypertension and an increase in the concentration of creatinine in the blood is noted.
• Chronic course is characterized in most patients by the so-called syndrome of vascular nephropathy, represented by a combination of arterial hypertension and moderate renal dysfunction, mainly filtration, with minimal urinary syndrome. A small number of patients with a chronic course of AFS-nephropathy has a nephrotic syndrome.

In patients with secondary antiphospholipid syndrome in systemic lupus erythematosus, nephropathy associated with an antiphospholipid syndrome is also possible, which in most cases is combined with lupus nephritis. There was no correlation between the presence of nephropathy associated with antiphospholipid syndrome and the morphological type of lupus nephritis. In patients with a combination of lupus nephritis and nephropathy associated with antiphospholipid syndrome, severe arterial hypertension and renal dysfunction are more common than in patients with isolated lupus nephritis, and morphological examination often reveals interstitial fibrosis. In a small proportion of patients with systemic lupus erythematosus, nephropathy associated with an antiphospholipid syndrome may be the only form of kidney 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 virtually simulate a picture of rapidly progressing lupus nephritis.