Nephrology for the Family Physician - O.I. Bakaliuk 2003

Renal Pathology in Other Diseases
The Kidneys in Collagenoses

Renal Involvement in diseases of other Organs and systems is frequently observed. This is accompanied by qualitatively distinct Changes in the urinary sediment (proteinuria, Hematuria, leukocyturia, cylindruria), which are combined with other clinical and laboratory signs of glomerular or tubular dysfunctions. Proper assessment of renal function in such situations plays a crucial role in prescribing an optimally effective Treatment regimen and, quite often, in determining the patient's prognosis for recovery.

In a significant number of cases, it is the state of The Kidneys in collagenoses that determines the patient's life prognosis.

Rheumatoid Arthritis. Renal damage in rheumatoid arthritis can occur as a manifestation of the disease itself, its complication, or as a consequence of The Use of baseline and symptomatic (nephrotoxic) agents.

The most common form of renal involvement in this condition is amyloidosis, which is detected in 11-60% of cases (V.N. Kovalenko et al., 1995). Furthermore, There is a direct correlation between The Development of amyloidosis, the degree of activity of the underlying disease, and the severity of erosive manifestations.

Renal Amyloidosis with the development of Nephrotic Syndrome is the most frequent cause of death in this category of patients. In addition, the rheumatoid process can lead to the development of specific rheumatoid Glomerulonephritis and ordinary Pyelonephritis.

The perception that rheumatoid glomerulonephritis is rare was quite widespread. This view was fostered by a limited number of observations, the potential for asymptomatic course of glomerulonephritis, the lack of immunochemical and electron microscopic verification of renal involvement symptoms, and the attribution of urinary syndrome solely to the nephrotoxic effects of medications.

The Study of this problem dates back to the 1940s, when light-optical Cell/15.html">Microscopy revealed proliferation of glomerular capillary endothelial Cells and the mesangium—glomerulitis—in patients with rheumatoid arthritis. Glomerular changes were accompanied by tubular alterations, such as tubular epithelium dystrophy and histiocytic infiltration of the peritubular space. Immunohistochemical studies revealed diffuse granular deposits of IMMUNOGLOBULINS of classes G and M, and Complement components—especially the C₃ component—in the glomerular capillary basement membrane, along with moderate deposits of immunoglobulins classes G, M, and fibrinogen in the mesangium.

Rheumatoid glomerulonephritis can follow a latent course or progress relentlessly and rapidly, resulting in fibroplastic transformation of glomerulonephritis with the development of glomerular sclerosis, tubular atrophy and fibrosis, and vascular hyalinosis.

The described clinical and laboratory symptoms of rheumatoid glomerulonephritis include edema syndrome (most commonly facial, scrotal, leg, and FOOT edema), proteinuria, hematuria, arterial Hypertension, nephrotic syndrome, isolated urinary syndrome (40-70%, R. Friedman, 1994), and tubular dysfunctions (32.9%, S.V. Tsybulko et al., 2000).

No clear correlation has been established between the duration of the disease, its degree of activity, morphological type, and the clinical manifestations of glomerulonephritis (G.P. Peklina, 1995), although it has been noted that rheumatoid glomerulonephritis, unlike renal amyloidosis, still tends to occur more frequently in patients with a shorter disease duration. However, this statement is not always valid: both rheumatoid glomerulonephritis and renal amyloidosis can manifest as early as the first year of the disease (I.E. Tareeva, 1983), and V.V. Serov (1977) regards rheumatoid glomerulonephritis as a pre-stage of amyloid renal involvement.

Thus, the existence of rheumatoid glomerulonephritis is beyond doubt, although its Diagnosis and Differential diagnosis from renal amyloidosis are challenging, especially in cases with modest clinical and laboratory symptoms.

It is also worth noting the relatively frequent (5-20%) risk of developing pyelonephritis in patients with rheumatoid arthritis against the Background of impaired immune reactivity, its progression to a chronic course, which also contributes to the development of Chronic Kidney Disease.

Renal involvement in Ankylosing spondylitis (Bechterew's disease) most frequently manifests as amyloidosis, which develops in 20-60% of cases and is the cause of death in 8-10% of cases, and less frequently as urolithiasis (10-20% of cases) due to purine METABOLISM disorders or the use of certain medications (immunosuppressants, Diuretics) (A.I. Dyadyk, 2001).

Systemic lupus erythematosus. Among systemic diseases in which renal involvement is frequent, single-organ, and sometimes even dominating, systemic lupus erythematosus must be mentioned first. Timely diagnosis of lupus glomerulonephritis is primarily important from a therapeutic standpoint, as this condition requires the prolonged administration of high doses of glucocorticoids and/or immunosuppressants with mandatory maintenance therapy.

The autoimmune nature of renal damage in systemic lupus erythematosus has been proven, although the specific etiological factor remains unidentified.

Lupus glomerulonephritis occurs As a result of the deposition of DNA-anti-DNA immune complexes on the glomerular capillary basement membrane due to the settling of circulating immune complexes and the in situ formation of immune complexes (A. Cohen et al., 1998). The latter is mediated by the binding of a highly charged DNA anion to the glomerular capillary basement membrane, followed by complex formation through the attachment of anti-DNA Antibodies. In any case, the cause of complex formation is circulating autoantibodies against DNA, and their Specificity for the phosphodiester bond—which is extremely widespread in the body—readily explains the systemic Nature of the damage. The formed DNA-anti-DNA complex is capable of activating The Complement System via the classical or alternative pathways, triggering an inflammatory response with subsequent tissue damage. In addition to these mechanisms, a certain role in renal damage during systemic lupus erythematosus is attributed to impaired (depressed) apoptosis (L. Rose et al., 1994; H. Sato et al., 1997).

Thus, The basis of renal involvement in systemic lupus erythematosus is immune complex glomerulonephritis, the Morphology of which is characterized by significant polymorphism. Lupus glomerulonephritis is essentially an obligatory mesangial glomerulonephritis, in which deposits are quite frequently represented by immunoglobulins of various classes (A, M, G) and complement components (C₃, C1q)—the so-called "full-house immunofluorescence". In addition to histological changes typical of conventional glomerulonephritis, lupus glomerulonephritis exhibits specific features: fibrinoid necrosis of capillary loops, karyorrhexis and karyopyknosis, the appearance of hematoxylin bodies, hyaline thrombi, "wire loops", and endothelially located virus-like inclusions in glomerular capillaries that resemble myxoviruses. Tubulointerstitial changes in lupus glomerulonephritis include the development of hyaline-droplet and vacuolar dystrophy of the tubular epithelium, its atrophy, and the accumulation of mononuclear cells in the interstitium and along the tubular basement membrane.

Clinically, lupus nephritis is detected in 35-90% of patients with systemic lupus erythematosus, most commonly 2-3 years after the onset of the first symptoms of the disease.

According to the latest WHO expert Classification (1995), the following morphological variants of lupus glomerulonephritis are distinguished:

Class I - normal light and electron microscopic appearance of glomeruli (IA), presence of class G immunoglobulins and various complement fractions on immunofluorescence microscopy (IB).

Class II - mesangial lupus glomerulonephritis; mesangial expansion (IIA), moderately pronounced hypercellularity (IIB).

Class III - focal segmental glomerulonephritis (with mild mesangial changes; with active necrotizing changes (IIIA), with active necrotizing and sclerosing changes (IIIB), with sclerosing changes (IIIC)).

Class IV - diffuse glomerulonephritis (marked mesangial and endocapillary proliferation, mesangial and subendothelial deposits); without segmental changes (IVA), with active necrotizing changes (IVB), with active sclerosing changes (IVC), with sclerosing changes (IVD).

Class V - membranous lupus glomerulonephritis; "pure" membranous glomerulonephritis (VA), in combination with mesangial glomerulonephritis (VB).

Class VI - advanced sclerosing glomerulonephritis.

THE SPECTRUM OF renal involvement in this condition is broad, ranging from transient proteinuria to rapidly progressive (subacute) GN and NS (A.Ya. Sygydyn et al., 1994). In some cases, there is a clear correlation between clinical manifestations—most of which are linked to glomerular damage—and the morphology of GN (R.J. Glassock et al., 1991).

From a clinical perspective, the following forms are distinguished:

- rapidly progressive lupus GN (10–12% of cases);

- nephritis with NS (30–40% of cases);

- active lupus GN with pronounced urinary syndrome (25–30% of cases);

- active lupus GN with minimal urinary syndrome (10–20% of cases).

Rapidly progressive GN is characterized by NS, hypertension, Early Development of renal failure, and an extremely poor prognosis (with 50% mortality among patients within the first two years of disease onset). It is worth noting that neither young patient age nor a relatively mild initial course of GN guarantees Immunity against sudden activation and rapid progression (I.E. Tareyeva et al., 1990). This necessitates careful outpatient monitoring of patients with any form of lupus GN and the initiation of active therapy at the slightest sign of disease exacerbation. Urinary findings are virtually indistinguishable from those in rapidly progressive GN of non-Collagen origin.

Features of lupus GN with NS include relatively low natriuresis, frequent coexistence with hypertension, hematuria, and cylindruria (hyaline, granular, and fatty casts). Aseptic pyuria (lymphocyturia) may also be observed. Hyper-$ ext{alpha}_2$-globulinemia and hypercholesterolemia are moderate.

Lupus GN with a pronounced urinary syndrome is characterized by proteinuria within the range of 0.5–1.0 g/day, persistent hematuria, and leukocyturia (lymphocyturia) in the absence of signs of a Urinary Tract infection.

In lupus GN with minimal urinary syndrome, proteinuria is negligible (up to 0.5 g/day) and leukocyturia is moderate, while clinical signs of renal involvement are absent.

In men, lupus GN tends to follow a more severe course and is frequently the direct cause of death (M.Yu. Folomeev et al., 1990).

A diagnosis of lupus GN is considered established if one or more of the following criteria are met (A.I. Dyadyk, 2001): mesangial, focal diffuse proliferative, or membranous GN identified in a renal biopsy; a persistent decrease in GFR by 30% or more over a year; or proteinuria exceeding 1 g/day.

If these findings are absent (or no renal biopsy has been performed), at least one of the following criteria is required for the diagnosis of lupus GN: a serum albumin level of 30 g/L or lower; proteinuria exceeding 0.5 g/day; the presence of hyaline, granular, and/or erythrocyte casts, and/or birefringent oval fat bodies in the urinary sediment; or persistent hematuria exceeding 5–6 red Blood Cells per high-power field.

Systemic sclerosis. Today, the term "scleroderma" encompasses a group of diverse nosological forms and syndromes characterized by the development of localized or generalized fibrosis. In addition to scleroderma proper, this group includes diffuse eosinophilic fasciitis, Buschke's scleredema, drug-induced (particularly by cuprenil) and chemical-induced sclerodermoid conditions, and paraneoplastic scleroderma syndrome. Closely associated with these are "major visceral" (retroperitoneal, pericardial, endocardial, endovascular, perivascular, mediastinal, pleuropulmonary, pulmonary) and "minor superficial" (Dupuytren's Contracture, Riedel's thyroiditis, orbital pseudotumor, Peyronie's Disease, keloids) fibroses, whose localization and Clinical presentation are reflected in their names.

The study of systemic sclerosis and related conditions opens up new Perspectives in clarifying the interplay between fibrogenesis, immune-mediated inflammation, microcirculatory disorders, genetic factors, and environmental influences in the Pathogenesis of any pathological process.

At the core of the pathogenesis of systemic sclerosis—the most prototypical representative of this group of diseases—are enhanced collagen and fibrogenesis resulting from altered functional activity of the fibroblast cell membrane, which represents a phenotypically stable trait. Upregulated Biosynthesis of type I and III collagens, glycosaminoglycans, Proteoglycans, and Fibronectin by fibroblasts, along with the acquisition of antigenic properties by these cells and subsequent autoimmune reactions, creates a "vicious circle" in the pathogenesis of this disorder (A.Ya. Sygydyn et al., 1994).

The involvement of immune mechanisms in the development of systemic sclerosis is also unquestionable, as evidenced by an imbalance in T-cell helper and suppressor activity, defective antibody-dependent cellular cytotoxicity, an increased frequency of autoantibodies (anticentromere, anticentriole, anti-Scl-70, anti-Scl-86), circulating immune complexes (CICs), and tissue lymphoplasmacytic infiltration (N.G. Guseva et al., 1995; S. Jablonska, 1998).

Another crucial pathogenetic link in scleroderma consists of cascading microcirculatory disorders resulting from vascular injury (endothelial destruction, smooth Muscle cell proliferation, predisposition to vasospasm, 60–95% of cases) and intravascular alterations (aggregation of cellular elements, increased blood viscosity and coagulability, 37–45% of cases).

The reduction in patency and lumen caliber of interlobular Arteries and arterioles—rather than of the main renal vessels—as well as the proliferation of renal stromal Connective Tissue elements with shunt formation in scleroderma, are currently quite convincingly linked to increased activity of the local renal (glomerular and tubular) renin-angiotensin-aldosterone system (RAAS), which provides a rationale for their pharmacological blockade (e.g., with ACE inhibitors or AT-II receptor antagonists).

Morphological changes in the kidneys in systemic sclerosis are diverse, though lesions of small- and medium-sized vessels predominate. Specific changes include hyperplasia of interlobular arteries with luminal narrowing, fibrinoid Necrosis of the glomerular afferent arterioles, and thickening of the glomerular capillary basement membrane (J.F. Donohoe, 1992). A characteristic phenomenon is also the reduction in the number of endothelial cell nuclei in the glomerular capillary loops, analogous to the changes observed in dermal capillaries. Tubular changes are non-specific and include epithelial Swelling, atrophy, foci of infiltration, ischemia, and interstitial fibrosis.

Risk factors for renal involvement include the disease course (acute or subacute), male gender, and middle age of the patient. The onset of renal involvement in scleroderma is unequivocally regarded as an unfavorable prognostic sign: according to the Institute of Rheumatology of the RAMS, the 15-year survival rate in scleroderma without renal involvement is 72%, whereas with renal involvement it is only 13% (N.G. Guseva, 1995).

According to N.G. Guseva (1995), two variants of renal involvement are distinguished: true scleroderma kidney and chronic scleroderma nephropathy, whereas D'Agati et al. (1994) encompass all forms of renal pathology under the term "scleroderma kidney."

Acute scleroderma kidney is characterized by a sudden onset, rapidly progressive urinary sediment abnormalities (resembling acute GN), and the development of severe arterial hypertension. Progressive renal failure leads to death within 1–2 months of the appearance of urinary abnormalities.

Depending on the severity of Renal Dysfunction and urinary sediment changes, chronic scleroderma nephropathy is divided into subclinical, moderate, and pronounced clinical variants.

The subclinical variant is characterized by intermittent proteinuria, microhematuria, cylindruria, and a slight decrease in GFR.

The moderate variant of chronic sclerodermatous nephropathy is characterized by minor yet stable changes in the urinary sediment, alongside a more pronounced decrease in GFR and renal concentrating ability.

The severe variant presents with edema, hypertension, persistently pronounced urinary syndrome, and a significant reduction in GFR.

Overall, all Variants of the chronic sclerodermatous kidney are characterized by a discrepancy between the severity of the urinary syndrome (which is moderate) and the decline in renal functional capacity (which is substantial) even in the Cytology/cytology/16.html">Early stages of the disease. The latter is detected using Zimnitsky's test, endogenous creatinine clearance tests, and isotope renography.

Sjögren's disease. Recently, clinicians' interest in both Sjögren's disease and Sjögren's syndrome has increased significantly, which is attributed to their frequent development in the context of other pathologies, including autoimmune, immune complex, and lymphoproliferative disorders. According to the WHO classification (1975, 9th Revision), Sjögren's disease is included in the group of diffuse connective tissue diseases.

The symptom complex, which includes keratoconjunctivitis sicca, xerostomia with decreased function of other secretory epithelial glands, was described in 1933 by the Swedish ophthalmologist H. Sjögren. Specifically, isolated sicca syndrome is regarded as an independent form of pathology, whereas Sjögren's syndrome is diagnosed when sicca syndrome is combined with collagenoses, active hepatitis, or Liver cirrhosis.

According to current concepts, Sjögren's disease is a systemic autoimmune disorder characterized by lymphoid infiltration of secretory exocrine glands, most frequently affecting the salivary and Sweat Glands. Its onset is associated with the primary impact of Viruses (cytomegalovirus, Epstein-Barr virus) against the background of a genetically determined predisposition, hormonal shifts, and an imbalance in the immunoregulatory cell system (V.N. Kovalenko et al., 1994).

The zone of lymphoid infiltration may not be restricted solely to the tissue of the epithelial glands, but can extend to the kidneys, the gastrointestinal tract, and the reticuloendothelial system, leading in some cases to the development of lymphoproliferative disorders (V.N. Vasiliev et al., 1982; V.G. Gracheva et al., 1998).

In addition to parotitis and recurrent Conjunctivitis, the clinical picture is characterized by arthralgia, arthritis, Raynaud's syndrome, lymphadenopathy, cryoglobulinemic and hypergammaglobulinemic purpura, and exudative Pleurisy (V.G. Gracheva et al., 1998).

Renal involvement in Sjögren's disease occurs more frequently in a subacute course (32.5%) and less frequently (15%) in a chronic course (V.N. Vasiliev et al., 1992). It is based on the appearance of analogous lymphocytic infiltrates in the mesangial structures, lymphocytic and necrotizing (less commonly) vasculitis, which causes predominant damage to the renal tubular apparatus (manifesting as Renal Tubular Acidosis, Aminoaciduria, and phosphaturia). Diffuse glomerulonephritis develops relatively rarely (more frequently in the presence of cryoglobulinemia and purpura).

Diagnosis of renal involvement in Sjögren's disease is generally straightforward and is based on The Emergence of urinary syndrome (moderate proteinuria, microhematuria, cylindruria), a decrease in renal concentrating function, and changes in urine pH. The prognosis is serious if diffuse glomerulonephritis (ultimately leading to renal failure) or lymphoproliferative disorders develop.

Renal involvement in the form of nephritis or nephropathy is defined as an obligatory component of Sharp's syndrome (G.G. Sharp) — a mixed connective tissue disease characterized by the presence of core symptoms typical of all major collagenoses. These include Raynaud's syndrome, polyarthritis, myositis, esophageal motility disorders, interstitial pulmonary fibrosis, scleroderma, Skin rash, fever, hepatosplenomegaly, lymphadenopathy, and polyneuropathy.