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

Tubulointerstitial Nephropathies

In recent years, considerable attention has been paid to interstitial pathology, with a focus on "interstitial diseases" affecting various organ localizations, primarily the Lungs and Kidneys. This is attributed to the fact that clinical medicine has acquired fundamentally new data regarding the Structure and function of Connective Tissue in these regions—the launching pad where all dystrophic, inflammatory, immune, and autoimmune processes take place.

From this perspective, the renal corpuscle serves as an ideal model for studying the mechanisms of intercellular interaction, since, as mentioned above, it comprises resident Cells of mesenchymal and epithelial origin, the GBM, and circulating Blood Cells (M.A. Paltsev et al., 1995). Therefore, following the chapters on "Dysmetabolic and Toxic Nephropathies" and "Renal Involvement in Other Diseases," we decided to include a separate chapter that summarizes the Current state of the art in tubulointerstitial renal disease.

Interest in disorders characterized by predominant involvement of the tubules and interstitial tissue arose long ago, and approximately 150 years ago, P. Rauer distinguished interstitial nephritis from the broader concept of "nephritis."

Currently, the term "tubulointerstitial nephropathies (TIN)" is generally accepted, which is explained by the broader meaning of the term. It encompasses not only inflammatory renal lesions, but also metabolic and toxic ones. In this context, it is understood that the disease is primarily driven by tubular aspects of the process, whereas vascular and glomerular changes (such as glomerulosclerosis with hyperazotemia) develop later.

In certain clinical scenarios, a tubulointerstitial component is distinguished separately, for instance, in chronic GN, infectious mononucleosis, Viral Hepatitis, urolithiasis, leukemias, malignant lymphomas, vasculitis, arterio- and arteriolosclerosis, radiation nephritis, hypercalcinosis, hypokalemia, amyloidosis, Gout, thyroiditis, Sjögren's syndrome, etc.

Understandably, the multi-etiological Nature of the factors leading to TIN development also dictates various morphological changes: destruction of the tubular GBM, dystrophic damage to tubular nephrocytes, edema and cellular infiltration of the renal stroma (predominantly lymphocytes, monocytes, and macrophages), and interstitial sclerosis. The frequency of these features varies across different Stages of the disease, with a tendency toward the progression of nephrocyte dystrophy, tubular atrophy, and interstitial sclerosis.

However, there is no doubt about the important role of immune mechanisms in both acute and chronic TIN.

E.N. Wardle et al. (1995) and F. Strutz et al. (1998) distinguish three phases in The Development of the Immune Response during interstitial injury: afferent, regulatory, and efferent. During the afferent phase, antigen expression occurs alongside the activation of immunocompetent cells that contribute to the HUMORAL IMMUNE RESPONSE (helper T-lymphocytes, B-cells) and produce large amounts of gamma-interferon and interleukin-2. In the regulatory phase, proliferation of stimulated T-lymphocytes and effector cells is observed, accompanied by the release of corresponding cytokines into the interstitium. The efferent phase involves interstitial injury by Antibodies and cytotoxic T-cells, as well as The formation of deposits. Antibodies directed against tubulointerstitial structures exhibit pronounced cytotoxic effects, activating The Complement System and chemotaxis. Granulocytic cells, which actively "pack" the interstitium in this case, induce fibroblast activation with the formation of infiltrates. Such activated fibroblasts differ significantly from those of a normal Kidney (with a predominance of the mitotic type—39% of the total number of fibroblasts, whereas in a healthy kidney this percentage does not exceed 2), hyperproducing Collagen. Cytokines identified within the infiltrates include interleukins (from interleukin-1 to interleukin-7), alpha, beta, and gamma interferons, and tumor necrosis factors alpha and beta. The process culminates in interstitial fibrosis.

To date, there is no universally accepted Classification of TIN. For instance, according to R.S. Cotran (1996), acute and chronic forms of TIN are distinguished. Acute forms include drug-induced renal injury, graft rejection, cryoglobulinemias, TIN in systemic lupus erythematosus, and infectious renal diseases; chronic forms encompass Metabolic Disorders, chronic PN, drug-induced nephropathies, heavy metal poisoning, renal involvement in neoplastic processes, hereditary Tubulopathies, and immune disorders with or without glomerular involvement (GN, Sjögren's syndrome, thyroiditis).

V.V. Serov et al. (1985) propose dividing TIN into infectious (resulting from Viruses, Bacteria, and Fungi) and non-infectious (primarily caused by agents that trigger hypersensitivity reactions). The Specific features of non-infectious TIN Pathogenesis—namely, The Emergence of a hypersensitivity reaction—serve as the rationale for distinguishing immune-complex, antibody-mediated, and Cell-mediated variants of TIN. The nosological criterion divides TIN into Primary and secondary. Based on their clinical course, TIN may be acute or chronic, each presenting with distinct morphological types. For acute TIN, these include edematous and cellular types with four subtypes (plasmacytic, eosinophilic, lympho-histiocytic, granulomatous, and tubulo-necrotic); for chronic TIN, they comprise cell-destructive and atrophic-sclerotic types.

B.I. Shulutko et al. (1985) believe that tubulointerstitial renal disorders comprise two independent diseases: one being acute, and the other chronic tubulointerstitial nephritis.

Acute tubulointerstitial nephritis is an immune, non-destructive, non-bacterial inflammation morphologically characterized by edema and plasmacytic-lymphocytic infiltration predominantly within the renal medulla, with secondary involvement of the glomeruli and vessels, and clinically manifested by acute ARF.

Chronic tubulointerstitial nephritis is a heterogeneous, multi-etiological disease characterized by a wave-like, non-bacterial, non-destructive course predominantly affecting the renal medulla, followed by its sclerosis and the involvement of all nephron structures. The clinical manifestations of chronic tubulointerstitial nephritis include benign Hypertension and urinary syndrome.

Below is the classification of TIN proposed by I.E. Tareeva (1995), which, in our view, is quite convenient for practical use. According to this classification, acute and chronic TIN are distinguished.

The pathogenesis of acute TIN is associated with the entry into the bloodstream of a toxic substance or bacterial toxin which, upon tubular reabsorption, damages their GBM. Following reabsorption, these Antigens trigger an immune response with the deposition of immune complexes within the interstitial tissue and capillary walls. Edema and inflammatory reactions developing in the interstitium lead to the compression of tubular vessels, elevated intratubular pressure, and, consequently, impaired BLOOD FLOW IN the renal cortex, followed by a decrease in the GFR. The outcome of such changes is a reduction in Water reabsorption (polyuria, hyposthenuria), while severe glomerular ischemia may lead to papillary necrosis with massive HE. Gradually, interstitial edema subsides, effective renal blood flow is restored, and both the GFR and urinary concentration processes normalize.

Acute TIN forms include: drug-induced, viral, bacterial, parasitic, and immune forms.

Acute drug-induced TIN are described by us in the chapter "Iatrogenic Renal Injury."

Among viral TIN, hemorrhagic fever with renal syndrome ranks first. The latter is diagnosed not only in the Far East, as previously reported, but also in Central European countries. The causative agent belongs to the vasculotropic ultra-viruses—the Hantaan virus in Asian countries, and the Puumala and Seoul viruses in European countries (K.C. Siamopoules et al., 1994).

A leading role in its pathogenesis is played by vascular wall damage accompanied by increased permeability, the development of serous-hemorrhagic inflammation in various Organs, hemorrhages, and impaired Functions of various systems and organs due to hyperhistaminemia, hyperserotoninemia, activation of the kallikrein-kinin system, and increased platelet aggregation capacity (A.A. Konstantinov, 1992; B.Z. Syrotin, 1994). Nonspecific histological Changes in the kidneys (interstitial nephritis, lymphoid-cell infiltration of the cortex and medulla) are complemented by specific ones—spontaneous cracks and ruptures of the cortical layer accompanied by the development of massive intrarenal or perirenal hematomas.

Characteristic clinical symptoms appearing within the first hours and days of the illness include hyperemia of the face, neck, and upper torso, injected scleral vessels, and facial, conjunctival, and eyelid edema. Renal involvement presenting as ARF (in 90% of cases) develops on days 5–7 of the disease, follows a severe course, and is fatal in 11–25% of cases (L.O. Glazun, 1993). In cases of recovery, impaired renal blood flow—such as slowed blood flow and glomerular hyperfiltration—is observed in these patients for a prolonged period (up to 1 year) (S.L. Zharsky et al., 2000).

Acute bacterial TIN fully corresponds to acute PN (primary or secondary).

A variant of parasitic TIN is leptospiral TIN, in which signs of renal impairment (oliguria, PU, cylindruria, HE, hypercreatininemia) are combined with symptoms of Liver damage (jaundice, hepatosplenomegaly) against the Background of a severe general condition.

Immune TIN, which are based on the deposition of immune complexes along the tubular endothelial GBM, include acute renal transplant rejection, renal involvement in cryoglobulinemia, and idiopathic forms. The clinical picture is dominated by moderately severe urinary syndrome combined with other signs (tubular dysfunctions, dysproteinemia, hypercreatininemia, low-grade fever, purpura, neuritis, arthralgia, hepatosplenomegaly).

There are several clinical Variants of the course of acute TIN (I. Dudar, 2001):

- the full-blown form, characterized by fever, eosinophilia, hypercreatininemia, and hyposthenuria. The duration of the disease is 3–4 months, with normalization of blood pressure by the first week, hypercreatininemia by the second week, and the renal concentrating function within 2–4 months;

- ARF with a typical presentation (anuria, hypercreatininemia, hyperkalemia, acidosis, etc.);

- &ldquoabortive&rdquo form (without anuria) characterized by the rapid onset of polyuria and moderate hypercreatininemia; the renal concentrating function recovers within 1.5&ndash2 months;

- &ldquofocal&rdquo form with mild clinical symptoms (decreased GFR to 40 mL/min, polyuria, hyposthenuria; no hypercreatininemia is observed).

Acute TIN may resolve with complete recovery or progress to chronic TIN. In certain cases, the disease takes an unremittingly progressive course ending in necrotizing nephrosis, which clinically manifests as ACUTE RENAL FAILURE and patient death within 2&ndash3 weeks.

In the pathogenesis of chronic TIN, immune mechanisms play a less significant role than in acute TIN. The direct Toxic Effect of the agent and accompanying metabolic disorders come to the foreground. Rarely, the genesis of chronic TIN is associated with the formation of antibodies against the tubular basement membrane. Morphological criteria of chronic TIN include diffuse interstitial infiltration, stromal sclerosis, the presence of colloid masses in the tubular lumens giving the appearance of a thyroidized kidney, loop atrophy, and ischemic glomerular wrinkling. The main Cells of the infiltrates are activated T Lymphocytes and plasmacytes. Scarring occurs diffusely or in patches. Heredity plays a certain role in the development of both chronic and acute TIN; The Role of Tamm-Horsfall protein in this process remains incompletely elucidated.

T. Murrey et al. (1995) distinguish the following variants of chronic TIN: associated with anatomical anomalies, analgesic, hyperuricemic, and hypertensive.

According to I.E. Tareieva (1995), the following groups of etiological factors for chronic TIN are identified: infections, medications, metabolic disorders, heavy metals, immune shifts, malignant neoplasms, and hereditary renal diseases.

L.A. Pyrih (1995) cites the following causes for the development of chronic TIN:

1. Immune-mediated diseases (systemic lupus erythematosus, cryoglobulinemia, Sjogren&rsquo and Goodpasture syndromes, Berger&rsquo disease).

2. Exposure to drugs and heavy metals (NSAIDs, Imuran, lithium, mercury, cadmium).

3. Infections (bacterial, viral, mycobacterial).

4. Obstructive processes (vesicoureteral reflux, mechanical obstruction).

5. Hematopoietic disorders (hemoglobinopathies, lymphoproliferative diseases).

6. Metabolic abnormalities (hyperuricemia, hyperoxaluria, hypercalcemia, cystinosis).

7. Granulomatoses (Wegener&rsquo granulomatosis, sarcoidosis, tuberculosis, candidiasis).

8. Vasculitides (inflammatory, sclerotic, embolic).

9. Congenital disorders (hereditary nephritis, sponge kidney, Polycystic Kidney Disease).

10. Endemic diseases (Balkan nephropathy).

11. Idiopathic chronic TIN.

B.I. Shulutko et al. (1985) propose other variants of chronic TIN: idiopathic, iatrogenic dysplastic, dysmetabolic, secondary to primary glomerulopathies or vascular renal diseases, and secondary to prolonged vascular ischemia.

Overall, the clinical picture of chronic TIN is defined by mild clinical signs combined with progressive tubular dysfunctions (acidosis, hyposthenuria, polyuria, glucosuria, Aminoaciduria, calciuria, tubular proteinuria, Fanconi Syndrome), while hyperkalemia is detected in the blood. Marked proteinuria and hypertension occur rarely, although B.I. Shulutko et al. (1985) indicate that hypertension and urinary syndrome proper reflect the earliest clinical manifestations of the disease. The course of chronic TIN is prolonged (spanning years); hypertension, as its early sign, typically stabilizes, steadily progresses, and leads to nephroangiosclerosis with CRF.

Let us briefly outline the main etiological groups of chronic TIN (variants according to B.I. Shulutko et al., 1985).

The Etiology AND PATHOGENESIS of idiopathic chronic TIN remain unknown. Men and women aged 25&ndash30 years are most commonly affected. The clinical picture is characterized by prolonged benign labile hypertension and persistent urinary syndrome. Morphological examination reveals medullary renal fibrosis, thickening of vessel walls, a sparse number of lymphoid infiltrates, thinning of the tubular basement membrane, and podocyte atrophy.

The development of iatrogenic chronic TIN is associated with The Use of numerous drug classes whose Mechanisms of action on renal structures vary&mdashfor example, simple accumulation of paracetamol in the medullary layer, the toxic effect of aspirin on intracellular enzyme systems of the tubular epithelium, the emergence of antibodies against the tubular epithelial basement membrane during antibiotic therapy, and proximal dysfunction up to the development of Fanconi syndrome due to cadmium exposure, etc.

Dysplastic chronic TIN is more frequently observed in childhood. Clinical symptoms are mild, dominated by moderately pronounced tubular dysfunctions that tend to decrease in severity with growth.

Dysmetabolic chronic TIN is well studied in hyperuricemia and multiple myeloma, as described above.

Chronic TIN developing against the background of diseases with a clearly defined autoimmune pathogenesis—such as systemic lupus erythematosus, Sjögren's syndrome, and chronic active hepatitis—is characterized by hyperkalemia, Renal Tubular Acidosis, and hyposthenuria.

Tubulointerstitial renal injuries can also be triggered by extrarenal tumors that secrete pathological Proteins, pressor amines, and Hormones, including malignant lymphomas, Lymphocytic Leukemia, and pancreatic tumors.

Secondary chronic TIN in primary glomerulopathies is quite difficult to differentiate from the tubulointerstitial component associated with these forms of pathology. However, such differentiation is essential, since M.Ya. Ratner et al. demonstrated as early as 1982 that the deterioration of renal function correlates more closely with tubulointerstitial changes than with glomerular ones, and The addition of TIN to glomerular pathology significantly alters the clinical picture and the patterns of its progression.

Despite similarities in the Clinical presentation and morphological changes, it should be noted that chronic TIN in this situation is more characteristically marked by more pronounced impairments in renal concentrating ability, increased excretion of ammonium, and hydrogen ions. The morphological picture frequently indicates an immune-mediated origin—such as the deposition of Class G IMMUNOGLOBULINS in tubular Tissues, the presence of antibodies against tubular basement membranes, and extraglomerular deposits (D. Lehman et al., 1995).

Chronic TIN arising in The Setting of prolonged hypertension (Essential Hypertension, Conn's syndrome, pheochromocytoma, etc.) is diagnosed infrequently. This is attributed to the fact that in the absence of a typical "renal" history, the diagnostic balance tends to tip in favor of essential hypertension. However, alongside connective tissue proliferation in the medulla, the presence of ischemically shrunken glomeruli, and thickening of the vascular walls, this type of TIN is characterized by lymphocytic infiltration of the renal medulla, which precludes interpreting the described changes solely as a consequence of vascular disorders.

Other forms of chronic TIN associated with electrolyte METABOLISM disorders—such as oxaluria, hypercalcemia, and hyperkalemia—are less well-known.

Renal involvement in oxaluria (oxalate nephropathy) typically develops in childhood as hereditary interstitial nephritis or urolithiasis.

The most frequent causes of hypercalcemia include hyperparathyroidism, sarcoidosis, neoplasms, vitamin D intoxication, and systemic calcinosis. Diagnostic criteria comprise nephrocalcinosis or small deposits of calcium salts in the renal parenchyma, which are primarily combined with a marked decrease in the renal concentrating function. The clinical picture is also typically characterized by polyuria, hyperazotemia, and arterial hypertension (the latter identified in 50% of cases).

Hyperkalemia leads to damage to the epithelium of the proximal tubules without alterations in the interstitial tissue. Functional impairments manifest as hyposthenuria, alterations in the acid-excreting function of the kidneys, and a tendency toward sodium retention.

The General Principles of TIN management involve withdrawing the offending toxic drug and stimulating its elimination from the body, desensitization in cases of immune-mediated pathogenesis, and the administration of supportive therapy. In 80% of cases, these measures are sufficient for patient recovery.

It is considered appropriate to prescribe ascorbic acid (0.5–1.0 g/day), rutin (0.1–0.2 g/day), tavegyl (0.003 g/day), and antioxidants (vitamin E 100–200 mg/day). A severe disease course warrants the inclusion of prednisolone (50–60 mg/day for 10–14 days), antiplatelet agents (curantyl 200–300 mg/day), low-molecular-weight heparins (fraxiparine – 0.3–0.6 mL/day), sorbents (enterosgel, syllard-P, fibrabet), saluretics, hemoperfusion, and hemodialysis (L.A. Pyrih, 1995; I. Dudar, 2001).