Scleroderma and kidney damage: causes

The causes of scleroderma have not been studied enough. At the present time in the development of the disease, environmental factors are of great importance. Adverse exogenous and endogenous effects (infections, cooling, drugs, industrial and household chemical agents, vibration, stress, endocrine disorders) appear to play a trigger role in the onset of the disease in people 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: impairment of immunity, microcirculation and fibro-formation. Excess 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 fibro-forming mechanisms. Interaction of these mechanisms among themselves is provided by cytokines, growth factors and other mediators, which are 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.

• Impaired immunity. In patients with different clinical forms of systemic scleroderma, various autoantibodies are detected with a high frequency, including specific antibodies-antigenic, antitopoisomerase (formerly known as aHm-Scl-70), anti-RNA polymerase, and ANCA, anti- endothelial, etc. The observed correlations between specific for systemic scleroderma autoantibodies, clinical manifestations and genetic markers of the disease suggest that the carrier of certain HLA antigens is associated with the synthesis of various antibodies and the formation of the fold subtypes of the disease. Thus, it has been established 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.
• Disturbance of microcirculation. An important role in the pathogenesis of systemic scleroderma is played by microcirculatory disorders. They are based on damage to the endothelium of small arteries, leading to vasospasm, platelet activation, development of intravascular coagulation of blood, proliferation of myointimal cells. The end result of these processes are vasoconstriction and tissue ischemia. The cause of activation of endothelial cells can be both immune-mediated damage (cytokines, antibodies), and the effect of non-immune factors (circulating proteases, oxidized lipoproteins, etc.). 
• Violation of fibro-formation. Vascular disorders precede fibrosis. In response to damage, endothelial cells release mediators that may activate perivascular fibroblasts. Fibroblasts of patients with systemic scleroderma synthesize excess amounts of fibronectin, proteoglycans and especially collagen types I and III, leading to the development of fibrosis. Platelets activated in areas of endothelial damage release growth factors that enhance the fibrosis process. Thus, excessive fibro-formation in systemic scleroderma is not a primary disorder, but rather the result of a complex effect of cytokines and other mediators on the endothelial and myointimal cells of the arteries and fibroblasts. Strengthening of fibrosis is promoted by ischemia of the tissue, which has developed as a result of endothelial damage, intravascular coagulation and vasospasm. Structural changes in the microcirculatory bed with systemic scleroderma are the basis of organ manifestations: skin, heart, lung, GIT, kidney damage, determining in most cases the prognosis of the disease.

[1], [2], [3], [4], [5], [6], [7], [8]

Pathomorphology of systemic scleroderma

At the heart of kidney pathology with systemic scleroderma is the lesion of the renal arteries of medium and small caliber. Morphological changes vary depending on the severity and severity of vascular lesion.

In acute scleroderma nephropathy macroscopically note the normal size and smooth surface of the kidneys. With the development of acute renal failure against a background of chronic lesions, the kidneys surface can be granular, with hemorrhagic crippling and multiple infarctions. Microscopically identify two types of acute vascular injury:

• edema, mucoid swelling and proliferation of intimal cells predominantly interlobular and to a lesser extent arched arteries;
• fibrinoid necrosis of arterioles, including those bringing and exuding, as well as glomerular capillaries, indistinguishable from changes that occur in malignant hypertension.

As a result of both types of damage, the lumen of the affected vessel significantly narrows, which is also facilitated by 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 intima of the arteries, fibrous thickening of adventitia and arteriolosclerosis.

With the development of severe acute scleroderma nephropathy, changes develop not only in the vessels, but also in the glomeruli. There are fibrinous thrombi in the gates of the glomerulus or in the lumen of the capillaries, which are focal or diffuse in nature, the phenomena of mesangiolysis, hyperplasia of cells of the South.

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

Along with vascular and glomerular changes in systemic scleroderma, tubulointerstitial tuberculosis is also noted. In severe cases of acute scleroderma nephropathy, these are cortical infarctions with parenchyma necrosis, in less severe cases, infarctions of small tubule groups. Chronic tubulointerstitial lesion is represented by tubular atrophy, fibrosis and lymphocytic infiltration of interstitium.

Clinical variants and pathogenesis of kidney damage in systemic scleroderma

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

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

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 intima of the arteries, fibrinoid necrosis of arterioles, intracapillary glomerular thrombosis, renal infarctions), which have a pronounced diffuse character, are constantly noted in patients with a 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 sclerosis of intima of arteries, arteriolosclerosis, glomerulosclerosis, canal atrophy and interstitial fibrosis are typical for patients with slowly progressing scleroderma nephropathy, clinically manifested by stable renal failure, moderate proteinuria with or without arterial hypertension. Similar changes can be observed in patients who underwent acute scleroderma nephropathy, after which the kidney function was not completely restored.

In addition to structural changes leading to a narrowing of the lumen of the vessels, a spasm of the small renal arteries contributes to the development of kidney ischemia, which increases the disturbances of the intrarenal blood flow. In patients with scleroderma nephropathy, functional vasoconstriction of intraorganic vessels is considered as a local renal equivalent of generalized Raynaud's syndrome. The mechanism of this phenomenon is not fully understood, however, the development of renal Raynaud's syndrome under the influence of cold, as shown in a number of studies, attests to the important role of the sympathetic nervous system.

A great importance in the genesis of renal pathology in systemic scleroderma is attached to the activation of the RAAS. Elevated plasma renin level was noted in patients with a true scleroderma kidney already in the onset of the process, as well as with moderate arterial hypertension in the case of chronic scleroderma nephropathy. This fact combined with a clear positive effect of ACE inhibitors in systemic scleroderma confirms the hypothesis of RAAS involvement in renal blood flow disturbance. The mechanism of this effect can be represented as follows. Functional vasoconstriction of the renal vessels lays down on their structural changes, leading to impaired renal perfusion. The resulting ischemia of the SOA is accompanied by an increase in renin secretion, the formation of an excessive amount of angiotensin II, which in turn causes general and locally renal vasoconstriction, exacerbating the already existing disorders. Thus, the 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 disease.

[9], [10], [11], [12], [13]