Nephrology for General Practitioners - O.I. Bakaliuk 2003

Dysmetabolic and Toxic Nephropathies
Kidneys and Gout

Addressing this issue, we must highlight the contribution to The Study of Gout made by our illustrious compatriot, the professor after whom the Ternopil Medical Academy is named — Ivan Yakovych Horbachevsky. In 1882, he synthesized uric acid for the first time, and between 1889 and 1891, he discovered the enzyme xanthine oxidase. His works laid the foundation for studying the METABOLISM of Nitrogenous Compounds and the pathology of purine metabolism.

The prevalence of gout has increased significantly in recent years, showing a clear parallelism between the level of hyperuricemia and the daily intake of meat and alcohol. According to various authors, the frequency of gout ranges from 0.04-2.8% depending on the region, while hyperuricemia ranges from 1.1-26.2% (V.A. Nasonova et al., 1987). Grout predominantly affects men, who are also diagnosed with hyperuricemia much more frequently (5-10:1).

The potential for Renal Involvement in gout and hyperuricemia has been known for a long time. These renal lesions are detected in 40-75% of patients with gout who have no clinical signs of joint involvement (O.V. Sinyachenko et al., 1986), and in 100% of cases when needle biopsy of the Kidneys is included in the diagnostic protocol (O.V. Sinyachenko, 1990, 1994).

At their core are the compensatory and ADAPTIVE REACTIONS OF the body aimed at maintaining a normal Blood uric acid level. It should be emphasized that The Nature and severity of renal damage determine the quality and life expectancy of patients with gout. Therefore, the notion that hyperuricemia is unlikely to cause renal injury in the absence of gouty Arthritis, and that initiating Treatment at a blood uric acid level below 0.586 mmol/L is impractical, has been discarded. Currently, hyperuricemia is defined as a uric acid level exceeding 0.420 mmol/L in men and 0.360 mmol/L in women (V.A. Nasonova, 1997).

It should also be considered that an elevated blood uric acid level in the Cytology/cytology/16.html">Early stages of the disease is accompanied by compensatory hyperuricosuria, which in itself is a risk factor for chronic tubulointerstitial nephritis. Morphological and immunohistochemical studies of renal biopsy specimens from individuals with so-called asymptomatic hyperuricemia have revealed varying degrees of interstitial fibrosis and signs of immune nephritis even before the clinical manifestations of gout appear (R.E. Rieselbach et al., 1992).

Overall, specific renal involvement in gout is characterized by the deposition of urates in the lumen of the tubules and collecting ducts, combined with the accumulation of monosodium urate crystals, monocyte-derived fibroblasts, giant Cells in the interstitium (microtophi), and thickening of the glomerular capillary basement membrane. In later stages, glomerular hyalinization and interstitial fibrosis with necrotic foci are observed. All these non-specific changes result from the action of a "trigger" factor (the uric acid crystal) on the target object — the resident macrophage, which is constantly present in the renal interstitium. Activation of the latter is accompanied by enhanced expression of "inflammatory" cytokines (interleukins-1, 6, 8, tumor necrosis factor alpha) and the release of Complement chemotactic fractions (C, C ). All these substances are potent stimuli for the infiltration of the interstitium by leukocytes of various classes — a constant source of BIOLOGICALLY ACTIVE SUBSTANCES (such as interleukins-1, 2, 4, 6, 8, tumor necrosis factor alpha, transforming growth factor beta; K. Matsushima et al., 1989; N.A. Mukhin et al., 1999), which selectively stimulate fibroblast proliferation while exerting an antimitogenic effect on differentiated cells. This manifests as disinhibition of the reabsorption system in the ascending limb of the Loop of Henle, increased sensitivity of receptors to antidiuretic hormone, expansion of circulating blood volume, elevated peripheral vascular resistance, activation of the sympathetic Nervous system, and the creation of conditions conducive to arterial Hypertension (A.S. Dondskov et al., 1999; J.C. Romero et al., 1988).

In addition to purely morphological aspects, immune alterations play a significant role in the Pathogenesis of gouty nephropathy. For instance, according to O.V. Sinyachenko et al. (1993) and G. Nuki (1993), the severity of glomerular damage in patients with gout correlates with a decrease in the number and functional activity of T-lymphocytes, hyperproduction of Class G IMMUNOGLOBULINS, and decreased synthesis of classes A and M immunoglobulins. Therefore, immune complex hyperuricemic nephritis has recently been quite reasonably added to the already known variants of renal involvement in gout (M.A. Maksimov et al., 1986). Along with the effects of microcrystallization and the direct toxic action of uric acid on the tubular epithelium, this condition exhibits glomerular changes characteristic of immune complex inflammation — deposition of immunoglobulin G and the C₃ fraction of the complement component along the glomerular capillary basement membrane, as well as subendothelial and mesangial deposits.

Tubular damage occurs more frequently with enhanced functional activity of T-lymphocytes and decreased synthesis of class A immunoglobulins, whereas interstitial changes are associated with reduced blood levels of circulating immune complexes and immunoglobulins of all classes. This imbalance worsens with the progression of renal failure, the first clinical signs of which appear 5-7 years after the onset of nephropathy (K. Kunev, 1990).

The literature contains isolated reports highlighting the Molecular and genetic mechanisms underlying The Development of gout — specifically, a determined impairment of DNA Repair processes (V.G. Filippova et al., 1987).

There are many causes of hyperuricemia: increased synthesis (primary gout, hyperuricemia associated with psoriasis, Polycystic Kidney Disease, sarcoidosis, amyloidosis, Chronic Glomerulonephritis, myeloproliferative disorders, use of Diuretics, salicylates, cytostatics, alcohol abuse, lead exposure), decreased uric acid excretion, and increased reabsorption either in isolation or combined with reduced excretion (V.N. Kovalenko et al., 1994).

Various classifications of gouty nephropathy exist. O.V. Sinyachenko et al. (1991) propose distinguishing the following types of gouty nephropathy: urolithiatic, latent, proteinuric, and hypertensive; whereas V.N. Kovalenko et al. (1994) classify it into urate Nephrolithiasis, chronic interstitial nephritis, and acute renal tubular obstruction.

Urate nephrolithiasis (affecting 10-30% of gout patients) has been known for a long time. Erasmus Roterodamus once wrote in a letter to his friend: "...you have gout, and I have kidney stones — we are married to sisters." This type of nephrolithiasis results from increased uric acid excretion against the Background of a persistently acidic urine reaction. The Clinical presentation of this condition is well known — Renal Colic followed by gross Hematuria, and the passage of calculi or gravel. It should be emphasized that due to the good solubility of uric acid salts, they may go undetected using standard urine sediment fixation Methods.

The Diagnosis of urate nephrolithiasis is based on clinical, laboratory (determination of uricemia levels, urine sediment composition), and instrumental (ultrasound, X-ray) methods.

Chronic interstitial nephritis in gout is characterized by Two Types of renal alterations:

- predominant interstitial infiltration, fibrosis, tubular atrophy, and vascular necrosis;

- accumulation of uric acid crystals in the interstitium or tubular lumen with The formation of microtophi.

Urinalysis findings do not differ significantly from those in Other forms of chronic interstitial nephritis — progressive microproteinuria, microhematuria (episodes of gross hematuria are possible), nocturia, and impaired urinary concentration ability. The onset of arterial hypertension (often accompanied by Early Development of vascular atherosclerosis), azotemia, and marked proteinuria indicates the progression of severe gouty nephropathy.

A questionnaire for diagnosing urate tubulointerstitial nephritis was proposed by I.M. Balkarov (1999).

Acute tubular necrosis with partial or complete Urinary Tract obstruction by urates results from uric acid crystallization in the distal renal tubules, collecting ducts, and renal pelves. Clinically, this is characterized by the development of ACUTE RENAL FAILURE, sometimes with severe consequences, triggered by a sudden and significant surge in hyperuricemia (provoked, for example, by meat-rich meals, alcohol, or the administration of massive doses of cytostatics, diuretics, etc.).

Gouty nephropathy is relatively easy to diagnose in the presence of Typical symptoms of gout. Difficulties arise when these symptoms are absent or when gouty nephropathy is the first (and often the only) manifestation of gout. In such cases, at least one typical symptom must be identified, the most informative being selective hyperuricemia (>0.420 mmol/L in men and >0.360 mmol/L in women) combined with a reduced uric acid clearance, the presence of calculi, uricosuria, oxaluria, and a burdened family history. These same criteria help differentiate other forms of interstitial nephropathy, chronic renal failure, and acute glomerulonephritis.

Early laboratory markers of renal injury in hyperuricosuria include microalbuminuria (>30 mg/day) and an elevated urinary level of N-acetyl-beta-D-glucosaminidase (>5 U/L, M.V. Lebedeva et al., 1998).

Management of gouty nephropathy. In general, hyperuricemia alone does not cause gout, and it remains unclear why, at the exact same blood uric acid level, some individuals develop gout while others do not. Nevertheless, underestimating this risk factor, as noted above, is quite dangerous.

Dietary therapy plays a paramount role in the management of gout and gouty nephropathy, aiming to maximally restrict the Dietary intake of Purines.

Permitted foods in gout include: milk and fermented dairy products, butter, vegetarian borschts and soups, dairy and fruit soups, white and dark bread, pasta and grain products (porridges, puddings, casseroles), vegetables (salads, vegetable hashes, juices, stewed, fried, and dried vegetables), fruits and berries (compotes, fruit jellies, juices), tea, nuts, sugar, jam, lard, blood sausage, cabbage, potatoes, cucumbers, carrots, onions, tomatoes, melons, watermelons, strawberries; foods to be limited include: eggs, boiled meat, fish, apples, apricots, grapes, olives, pears, peaches, cherries, oranges; non-recommended foods include: sausage products (especially Liver sausage), liver, kidneys, Brain, Tongue, veal, goose and duck meat, mutton, sprats, sardines, sprat (kilka), cod, zander, pike, herring, meat and fish broths, sauces, canned goods, smoked and spicy appetizers, spices (horseradish, mustard, pepper), raspberries, spinach, sorrel, cauliflower, rhubarb, legumes (peas, beans), mushrooms (porcini, champignons), natural coffee, cacao, and alcohol.

A.Ya. Huberrits et al. (1989) suggest a one-day menu for patients with gout: on an empty Stomach — warmed alkaline mineral Water (100 mL) or rosehip decoction (100 mL); first breakfast — thin milk oatmeal (150 g) and milk (200 mL); second breakfast — tomato juice (200 mL); lunch — vegetable soup (150 g) and milk-based fruit jelly (150 g); afternoon snack — carrot juice (200 mL); dinner — milk rice porridge (150 g), fruit compote (180 g); before bedtime — kefir (200 mL) or tea with milk without sugar (180 g). Fasting days (once a week) — such as cottage cheese-kefir, dairy-kefir, or vegetable days — are considered beneficial for gout.

According to their MECHANISM OF ACTION, antigout drugs are divided into uricostatics (which reduce uric acid synthesis) and uricosurics (which block uric acid reabsorption in the renal tubules).

Allopurinol (milurit, cyloric, cyloprim, apurin, granumet)—an inhibitor of xanthine oxidase, hypoxanthine-guanine phosphoribosyltransferase, and orotidine decarboxylase—is the most widely used uricostatic agent. Its initial dose is 300 mg/day (rarely 400–600 mg/day), and the maintenance dose is 100 mg/day. Allopurinol therapy is primarily indicated for severe hyperuricemia, gouty nephropathy with renal impairment, and uric acid stones.

Thiopurinol, an allopurinol derivative, inhibits glutamine-guanine phosphoribosyltransferase and is administered at a dose of 300–400 mg/day.

Hepatocatalase is less effective than allopurinol; its daily dose ranges from 10,000 to 25,000 IU administered intramuscularly 2–3 times a week.

Orotic acid inhibits The activity of 5-phosphoribosyl pyrophosphate, an enzyme that regulates The rate of pyrimidine nucleotide formation, which also serves as a building block for Nucleic Acids. It also exhibits a moderate hypocholesterolemic effect at a daily dose of 2–5 g; therapy is typically administered in courses of 20–30 days, 4–5 times a year. While orotic acid cannot replace allopurinol, it significantly potentiates its action and is frequently used when a reduction in the allopurinol daily dose is necessary (V.K. Hryn, 1998).

A certain reduction in uricemia can be achieved through phytotherapy (potato and celery decoction) (O.V. Syniachenko, 2001).

Prominent uricosuric agents include sulfinpyrazone (anturan), probenecid (benemid), etamid, normurat, benzbromarone, benziodarone, kebuzone, and tribuzone.

Anturan is prescribed at a daily dose of 200–400 mg, benemid at 0.5–2.0 g, etamid at 2.1–2.8 g, and normurat at 100 mg.

Probenecid is also an effective blocker of uric acid reabsorption. It is prescribed at an initial daily dose of 500 mg, gradually increased to 1000 mg/day, provided there is adequate Hydration (J. Canoso et al., 1996).

The Use of all uricosuric agents must be combined with adequate fluid intake (2–3 L/day) of alkalinizing solutions. To alkalinize the urine, daily consumption of 1–2 lemons, alkaline mineral waters, and blemaren (blemaren, manufactured by Esparma, Germany, contains citric acid, potassium bicarbonate, and sodium citrate) is recommended. Notably, urine alkalinization is contraindicated during acute exacerbations of renal failure.

The choice of medication is determined by the type and severity of hyperuricemia, as well as the functional state of the kidneys. In metabolic-type hyperuricemia with adequate uricosuria, the drugs of choice are uricodepressive agents, including the purine antagonist azathioprine. For the renal type, uricosuric agents are preferred (in the absence of urolithiasis, gastric or duodenal ulcers, liver disease, or gouty nephropathy). In the latter cases, only uricodepressive drugs are used. For patients intolerant to allopurinol or probenecid (elderly individuals, patients with Chronic Kidney Disease or Heart Failure), prescribing colchicine at 0.6 mg/day is entirely justified (J. Canoso et al., 1996), as it provides reliable prophylaxis against acute gout flares.

Literature data indicate the potential usefulness of enterosorption in the complex management of gout, aimed at reducing uric acid reabsorption in the gastrointestinal tract (A.A. Matulis et al., 1987; O.V. Syniachenko, 2001).

Below we outline promising directions in the treatment of gouty nephropathy.

In 1992, M. Nakashima et al. reported that cozaar, a next-generation antihypertensive drug and type 1 angiotensin II receptor blocker, exhibits not only blood pressure-lowering effects but also hypouricemic and uricosuric properties. These effects of cozaar have been demonstrated in both volume-dependent and volume-independent patients with hypertension. Although the exact mechanism of action is not yet fully elucidated, it has been established that increased uric acid excretion (without precipitating acute renal blockade) is unique to cozaar, whereas its metabolite E-3174 lacks this effect. These critical properties of cozaar are exceptionally beneficial for treating gouty nephropathy by simultaneously targeting hypertension, hyperuricemia, and uricosuria.

Urate nephrolithiasis and chronic interstitial nephritis are managed according to General Principles. A mandatory prerequisite for preventing and treating acute tubular necrosis and acute urate nephropathy is maximizing the solubility of uric acid crystals through intensive dilution (high fluid intake), alkalinization (see above, plus the use of citrosoda, or less frequently, acetazolamide—a Carbonic anhydrase inhibitor), and Forced diuresis (furosemide) (I.M. Balkarov et al., 1990). In cases of acute renal failure, early hemodialysis should be the method of choice.

Finally, it must be emphasized that even adequate correction of uricemia at the stage of established renal damage cannot fundamentally alter its clinical course; therefore, preventive measures play a decisive role here.