Scleroderma and kidney damage - Causes

The causes of scleroderma have not been sufficiently studied. Currently, significant importance is attached to environmental factors in the development of the disease. Unfavorable exogenous and endogenous influences (infections, cooling, drugs, industrial and household chemical agents, vibration, stress, endocrine disorders) apparently play a triggering role in the development of the disease in individuals with a genetic predisposition. The latter was confirmed by the detection of certain histocompatibility antigens: HLA A9, B8, B35, DR1, DR3, C4A and others - in patients with scleroderma.

The pathogenesis of scleroderma includes three main links: impaired immunity, microcirculation, and fibrosis. Excessive accumulation of collagen-rich extracellular matrix in the skin and internal organs in systemic scleroderma is the final stage of a complex pathogenetic process that combines immune, vascular, and fibrosis mechanisms. The interaction of these mechanisms is ensured by cytokines, growth factors, and other mediators produced by lymphocytes, monocytes, platelets, endothelial cells, and fibroblasts. In recent years, the role of immune disorders in the development of vascular damage and fibrosis in systemic scleroderma has been established.

• Immune dysfunction. In patients with different clinical forms of systemic scleroderma, various autoantibodies are detected with high frequency, including specific ones - angiogenesis, antitopoisomerase (previously known as aHm-Scl-70), anti-RNA polymerase, as well as ANCA, antiendothelial, etc. The discovered correlations between autoantibodies specific to systemic scleroderma, clinical manifestations and genetic markers of the disease suggest that the carriage of certain HLA antigens is associated with the synthesis of various antibodies and the formation of different subtypes of the disease. Thus, it was found that anti-RNA polymerase autoantibodies in the diffuse cutaneous form of systemic scleroderma can be associated with a high frequency of kidney damage and an unfavorable prognosis, and ANCA is more often detected in patients with chronic renal failure.
• Microcirculation disorders. Microcirculatory disorders play an important role in the pathogenesis of systemic scleroderma. They are based on damage to the endothelium of small arteries, leading to vasospasm, platelet activation, development of intravascular blood coagulation, and proliferation of myointimal cells. The end result of these processes is vasoconstriction and tissue ischemia. The cause of endothelial cell activation can be both immune-mediated damage (cytokines, antibodies) and the impact of non-immune factors (circulating proteases, oxidized lipoproteins, etc.).
• Impaired fibroformation. Vascular abnormalities precede fibrosis. In response to injury, endothelial cells release mediators that may activate perivascular fibroblasts. Fibroblasts from patients with systemic sclerosis synthesize excessive amounts of fibronectin, proteoglycans, and especially collagen types I and III, leading to fibrosis. Platelets activated at sites of endothelial injury release growth factors that enhance fibrosis. Thus, excessive fibroformation in systemic sclerosis is not a primary disorder but rather the result of the combined effects of cytokines and other mediators on arterial endothelial and myointimal cells and fibroblasts. Fibrosis is enhanced by tissue ischemia resulting from endothelial injury, intravascular coagulation, and vasospasm. Structural changes in the microcirculatory bed in systemic scleroderma underlie organ manifestations: lesions of the skin, heart, lungs, gastrointestinal tract, kidneys, determining in most cases the prognosis of the disease.

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Pathomorphology of systemic scleroderma

The basis of kidney pathology in systemic scleroderma is damage to the renal arteries of medium and small caliber. Morphological changes vary depending on the severity and severity of the vascular lesion.

In acute scleroderma nephropathy, normal kidney sizes and a smooth surface are observed macroscopically. In the development of acute renal failure against the background of chronic damage, the surface of the kidneys may be granular, with hemorrhagic specks and multiple infarctions. Microscopically, two types of acute vascular damage are detected:

• edema, mucoid swelling and proliferation of intimal cells, mainly of the interlobular and, to a lesser extent, arcuate arteries;
• fibrinoid necrosis of arterioles, including afferent and efferent ones, as well as glomerular capillaries, indistinguishable from the changes that occur in malignant arterial hypertension.

As a result of both types of damage, the lumen of the affected vessel narrows significantly, which is also facilitated by the aggregation and fragmentation of erythrocytes, reflecting the processes of thrombotic microangiopathy. A sharp narrowing of the vessels leads to ischemia of the perfused tissue. Chronic vascular changes are represented by fibroelastosis of the arterial intima, fibrous thickening of the adventitia and arteriolosclerosis.

In the development of severe acute scleroderma nephropathy, changes develop not only in the vessels, but also in the glomeruli. Fibrin thrombi in the glomerular hilum or in the lumen of the capillaries, focal or diffuse in nature, mesangiolysis, and hyperplasia of the JGA cells are observed.

Chronic changes in the glomeruli are represented by glomerulosclerosis, similar to that observed in diseases occurring with intravascular coagulation of the blood and ischemia of the glomeruli - hemolytic uremic syndrome and malignant arterial hypertension.

Along with vascular and glomerular changes in systemic scleroderma, tubulointerstitial changes are also observed. In severe cases of acute scleroderma nephropathy, these are cortical infarctions with parenchyma necrosis, and in milder cases, infarctions of small groups of tubules. Chronic tubulointerstitial damage is represented by tubular atrophy, fibrosis, and lymphocytic infiltration of the interstitium.

Clinical variants and pathogenesis of kidney damage in systemic scleroderma

Scleroderma nephropathy is a vascular pathology of the kidneys caused by occlusive damage to the intrarenal vessels, leading to organ ischemia and manifested by arterial hypertension and renal dysfunction of varying severity. There are two forms of kidney damage in systemic scleroderma - acute and chronic.

• Acute scleroderma nephropathy (syn. - true scleroderma kidney, scleroderma renal crisis) is acute renal failure that develops in patients with systemic scleroderma in the absence of other causes of nephropathy and occurs in most cases with severe, sometimes malignant arterial hypertension.
• Chronic scleroderma nephropathy is a low-symptom pathology, which is based on a decrease in renal blood flow with a subsequent decrease in SCF. In the early stages of the disease, this is determined by endogenous creatinine clearance (Reberg test) or isotope methods. As a rule, a decrease in SCF is combined with minimal or moderate proteinuria, arterial hypertension and initial signs of chronic renal failure are often noted.

In the pathogenesis of both forms of scleroderma nephropathy, the main role is played by vascular disorders, both structural and functional. Acute pathomorphological changes (mucoid swelling of the arterial intima, fibrinoid necrosis of arterioles, intracapillary glomerular thrombosis, renal infarctions), which are of a pronounced diffuse nature, are constantly observed in patients with true scleroderma kidney, including in the absence of severe arterial hypertension. Focal acute changes can in some cases be detected in patients with moderate renal failure, arterial hypertension or proteinuria. Chronic changes in the form of arterial intimal sclerosis, arteriolosclerosis, glomerulosclerosis, tubular atrophy and interstitial fibrosis are characteristic of patients with slowly progressive scleroderma nephropathy, clinically manifested by stable renal failure, moderate proteinuria with or without arterial hypertension. Similar changes can be observed in patients who have had acute scleroderma nephropathy, after which renal function has not fully recovered.

In addition to structural changes leading to narrowing of the lumen of the vessels, spasm of small renal arteries also contributes to the development of renal ischemia, increasing disturbances of intrarenal blood flow. In patients with scleroderma nephropathy, functional vasoconstriction of intraorgan vessels is considered a local renal equivalent of generalized Raynaud's syndrome. The mechanism of this phenomenon is not fully understood, but the development of renal Raynaud's syndrome when exposed to cold, proven in a number of studies, indicates an important role of the sympathetic nervous system.

Activation of RAAS is of great importance in the genesis of renal pathology in systemic scleroderma. Increased plasma renin levels are noted in patients with true scleroderma kidney already at the onset of the process, as well as in moderate arterial hypertension in the case of chronic scleroderma nephropathy. This fact, combined with the clear positive effect of ACE inhibitors in systemic scleroderma, confirms the hypothesis of the participation of RAAS in the disruption of renal blood flow. The mechanism of this effect can be represented as follows. Functional vasoconstriction of the renal vessels is superimposed on their structural changes, leading to impaired renal perfusion. The resulting ischemia of the JGA is accompanied by increased renin secretion, the formation of excess angiotensin II, which, in turn, causes general and local renal vasoconstriction, aggravating the existing disorders. Thus, activation of RAAS in scleroderma nephropathy is a secondary phenomenon, which, however, makes an important contribution to the formation of a vicious circle of vasoconstriction and vascular damage underlying renal pathology.

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