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

Dysmetabolic and Toxic Nephropathies
Iatrogenic Renal Injuries

Iatrogenic renal pathology tends to increase due to the widespread use of aggressive therapeutic modalities, including glucocorticoids, immunosuppressants, NSAIDs, Antibiotics, and Vaccines.

It should be noted that virtually every pharmacological agent can affect renal function in one way or another (L.A. Pyrih, 1996); however, the extent of this impact depends on its Site of Action. These sites may include: renal hemodynamics, glomerular ultrafiltration processes, tubular metabolic and transport systems, direct nephrotoxic effects, potential induction of other Urinary Tract disorders, impairment of renal hormonal function, allergy with subsequent immune-mediated inflammation, interstitial injury, and anaphylactic Shock complicated by collapse.

The site of xenobiotic action on the Kidneys is well explained by the hypothesis proposed by D.A. Coechel et al. (1995), according to which its nephrotoxicity depends on the presence of two chemical groups in its Structure: carboxyl and alkylated groups. The carboxyl group drives xenobiotic accumulation within proximal tubular Cells via the well-known organic anion secretory transport system, whereas the alkylated group drives the alkylation of tubular Cell components, leading to their subsequent destruction.

According to M.S. Komadenko et al. (1989), based on intravital morphological studies of the kidneys, drug-induced nephropathy is largely driven by organismal sensitization against the Background of congenital or acquired Renal Dysfunction. This sensitization is accompanied by an upregulation of immunoglobulin E production, resulting in The formation of drug-Protein Complexes and anaphylaxis mediators. Subsequently, the prostaglandin and kallikrein-kinin systems become involved, leading to impaired local hemodynamics, edema development, and interstitial damage. Consequently, the Clinical presentation of iatrogenic renal injury is extremely diverse.

Other probable mechanisms of drug-induced nephropathy involve the upregulated expression of Major Histocompatibility Complex Antigens and substance adhesion molecules on renal cellular structures, potentially mediated by gamma-interferon and other pro-inflammatory cytokines (F. Mampaso et al., 1993).

I.Yu. Nikolaev et al. (1988) distinguish between acute and chronic drug-induced injuries.

Acute injuries include acute tubulointerstitial nephritis, acute tubular necrosis, acute drug-induced membranous Glomerulonephritis, necrotizing renal vasculitis, bilateral cortical necrosis, intrarenal blockade by drug crystals or macromolecules, and electrolyte-hemodynamic (functional) renal failure.

Chronic injuries include chronic interstitial nephritis, potassium-losing nephropathy, acquired Fanconi Syndrome, nephrogenic diabetes insipidus, Nephrotic Syndrome, Nephrolithiasis, and retroperitoneal fibrosis.

Antibiotics, particularly Aminoglycosides, are the most frequent cause (40 %) of acute drug-induced nephropathies. In order of increasing nephrotoxicity, antibiotics are ranked as follows: penicillin, streptomycin, kanamycin, tobramycin, gentamicin, and neomycin. Nephropathies occur especially often (in 35 % of patients) when aminoglycosides are combined with furosemide or cephalosporin antibiotics (T. Nykula, 2001). The Pathogenesis of antibiotic-induced renal injury involves allergic and toxic mechanisms. The toxic effect is manifested directly and/or indirectly through impaired hemodynamics, microcirculation, and METABOLISM—such as the disruption of nucleic acid synthesis in the proximal tubular epithelium, competitive inhibition of mitochondrial carnitine transport, and suppression of Transmethylation processes, among others.

A frequent clinical manifestation in these cases is acute tubular necrosis accompanied by moderate oliguria, hyposthenuria, natriuresis, minimal proteinuria, and microhematuria. Renal failure progresses gradually and may be reversible upon drug withdrawal. Cephalosporins can also lead to acute tubular necrosis, with their nephrotoxicity increasing when combined with Diuretics.

Other antibacterial agents—such as Penicillins, rifampicin, Tetracyclines (especially expired ones), and sulfonamides—more commonly damage the kidneys via acute tubulointerstitial nephritis. The latter is characterized by a sudden onset, fever, polyuria, and lower back pain. An important clinical hallmark of acute drug-induced tubulointerstitial nephritis is a recurrent fever following initial normalization (!), frequently accompanied by eosinophilia and allergic Skin lesions. Urinalysis reveals Hematuria, proteinuria (typically up to 1 g/day), and aseptic leukocyturia (predominantly driven by eosinophils). The Glomerular Filtration rate is generally reduced, although oliguria does not occur. This clinical syndrome is driven by a delayed-type hypersensitivity reaction.

Acute drug-induced interstitial nephritis features a favorable prognosis, with symptom regression coinciding with drug discontinuation.

NSAIDs (indomethacin, aspirin, ibuprofen, piroxicam) and non-narcotic analgesics (analgin, phenacetin, paracetamol) rightfully occupy second place in the frequency of drug-induced nephropathies (10–20 %). Renal injury in these cases can follow either pattern and occur with any drug, regardless of the duration of use (ranging from several days to several months).

Acute renal injuries are primarily associated with the aforementioned agents' impact on renal hemodynamics via prostaglandin synthesis inhibition. Risk factors include Liver and renal disease, hyponatremia, hypovolemia, diuretic therapy, Heart Failure, arterial Hypertension, systemic lupus erythematosus, postoperative status, advanced age, and the concurrent use of two or more drugs from this group (noting that the combination of paracetamol with other analgesics is particularly unfavorable). The most common renal effect of NSAIDs and non-narcotic analgesics is a disturbance in the Water-electrolyte balance, leading to hyperkalemia. Risk factors for hyperkalemia include Diabetes Mellitus, multiple myeloma, and ACE inhibitor therapy (A. Whelton et al., 1991). Local hemodynamic shifts (reduced renal Blood flow and glomerular filtration rate) combined with transient hypercreatininemia are more commonly observed with indomethacin use.

In some cases, hemodynamic shifts are extremely severe, leading to acute tubular necrosis with ACUTE RENAL FAILURE. Notably, acute renal failure can develop over varying timeframes—from several hours to several months (S.F. Wen et al., 1992).

Acute renal failure caused by radiocontrast agents is relatively common (4–16 %). These agents can either directly affect the renal tubular epithelium or induce hyperuricemia.

The administration of radiocontrast agents against the background of indomethacin therapy is particularly hazardous regarding the onset of acute renal failure. Its pathogenesis is critically driven by the spasm of afferent glomerular arterioles with a drop in the glomerular filtration rate, caused by hypercalcemia, blockade of prostaglandin synthesis, activation of the renin-angiotensin-aldosterone system, and increased adenosine activity (F.U. Dzhgoeva et al., 1995).

The literature describes cases of acute renal failure resulting from The Use of anticoagulants, sulfonamides, uricostatics, and antitubercular drugs.

Acute drug-induced membranous glomerulonephritis is diagnosed primarily in rheumatoid Arthritis patients treated with gold salts or cuprenil, and rarely in hypertensive patients treated with captopril (Yu.O. Pospishil, 1997).

In some cases, drugs from various groups cause transient functional disorders (such as a decrease in effective renal plasma flow and glomerular filtration rate, or The Development of hyperaldosteronism, hyperkalemia, and hypercreatininemia).

Among the chronic forms of drug-induced renal injury, chronic tubulointerstitial nephropathy (TIN) is quite common. The Role of immune shifts in this condition is minimal, as it primarily involves the direct Toxic Effect of the drug: Metabolic Disorders, impaired tissue Respiration processes, and disrupted activity of renal substance transport enzyme systems, accompanied by corresponding morphological changes (diffuse lymphoid infiltration of the interstitium, stromal sclerosis, and Atrophy of the tubular epithelium).

The clinical picture of chronic TIN is determined by progressive proximal and/or distal tubular dysfunctions: acidosis, hyperkalemia, hyposthenuria, polyuria, nocturia, and episodes of gross hematuria accompanied by typical Renal Colic. As the condition progresses, glomerular symptoms (arterial hypertension, proteinuria) join the picture, presenting as focal segmental glomerulosclerosis/hyalinosis leading to renal failure. In 1/3 of cases, transient acute renal failure develops with rapid spontaneous recovery of renal function.

Analgesic nephropathy is the most frequent form of chronic TIN. It is a drug-induced tubulointerstitial disease characterized by a progressive clinical course and bilateral renal atrophy, frequently accompanied by papillary necrosis. It accounts for 0.1–4 % of renal injury cases in European countries and 10–20 % in Australia. The Link Between analgesic (phenacetin) use and renal pathology was first established in 1955 by H.U. Zollinger, and THE CONCEPT OF "analgesic syndrome" was formulated in 1986 by F. Gutzwiller et al.

Aside from renal impairment, Clinical Features of this syndrome include gastrointestinal, hematological, cardiovascular, and neuropsychiatric disorders, gonadal dysfunction, characteristic skin pigmentation, and premature Aging (P. Kincaid-Smith, 1988).

The proportion of the population regularly taking analgesics ranges from 3 % to 6.8 % (F. Gutzwiller et al., 1986). Analgesic nephropathy is more prevalent among women aged 35–60 who have used various types of analgesics for extended periods, sometimes without proper supervision, at doses of 1 g/day or more. Most reports attribute the development of analgesic nephropathy to the prolonged use of aspirin, paracetamol, amidopyrine, butadione, and rheopyrine, with 80–85 % of cases manifesting strictly as papillary necrosis. Furthermore, There is a direct correlation between the drug dose and the severity of clinical and laboratory manifestations of renal injury. According to A. Zalkalns et al. (1990), the absolute risk of renal injury from NSAIDs and "pure" analgesics ranges from 59 to 175 cases per 1,000 population with prolonged use, and from 1.8 to 22 cases with episodic use.

Analgesic nephropathy presents with polyuria and a mild urinary syndrome. Its early signs include a decreased relative urine density (in 100% of cases) and impaired urinary acidification (25% of cases); in 10% of cases, clinical features of Renal Tubular Acidosis develop (Muscle weakness, cramps, medullary sponge Kidney calcification, and urolithiasis).

A distinctive clinical feature of analgesic nephropathy is The high frequency of arterial hypertension (up to 60%) and renal colic attacks (30%). Aseptic pyuria is detected in 70% of patients, urinary tract infections in 30%, and urinary tract tumors in 10%. Notably, urinary tract tumors (especially of the bladder) are diagnosed 10 (!) times more frequently in patients who abuse analgesics than in the general population.

The nephrotoxicity of diuretics—a Class of drugs prescribed in routine general practice almost daily—also warrants consideration. Yu.S. Milovanov et al. (1995) reported that furosemide administration over 2–3 weeks led to acute renal failure (ARF) in 22 out of 692 patients (3.18%). Furthermore, diuretics have been shown to potentiate the nephrotoxicity of other medications (such as cephalosporins, NSAIDs, aminoglycosides, corticosterone, and immunosuppressants).

Renal damage is more likely to occur with prolonged diuretic use (ranging from 2 weeks to 6 months). Risk factors include advanced age, hypertension, and baseline renal impairment. Patients exhibit signs of impaired urinary concentration capacity combined with a reduced glomerular filtration rate (GFR) and hypercreatininemia.

Several mechanisms of diuretic-induced toxicity can be distinguished. First, we highlight metabolic effects—such as hyperuricemia with all its adverse consequences (G.A. Glezer, 1993; Ya.F. Zverev et al., 1999), metabolic acidosis induced by Carbonic anhydrase inhibitors, electrolyte imbalances (primarily affecting calcium, potassium, and sodium), and the blockade of enzyme sulfhydryl groups by ethacrynic acid—which are further potentiated by hypovolemia and the redistribution of intrarenal blood flow (Yu.S. Milovanov et al., 1995; V.M. Bryukhanov et al., 1998; R.A. Oven et al., 1993). Additionally, prolonged diuretic use increases the risk of Renal Tumors (R.A. Hiatt et al., 1994), although research in this area is ongoing.

The development of chronic tubulointerstitial nephritis (TIN) may also be triggered by gold preparations (auranofin, chrysanol, aurophan). "Gold-induced" TIN manifests as a decreased GFR combined with proteinuria and hematuria, and occasionally nephrotic syndrome. Renal biopsies reveal features of immune-complex glomerulonephritis with gold inclusion granules in the Lysosomes and Mitochondria of epithelial cells (T.D. Nikula, 2001).

Summing up the above, we present the following Classification of drug-induced nephropathies based on the etiological factor (I.M. Gandzha, 1983; C.R.V. Edwards et al., 1994).

Drug-induced nephropathy can be triggered by the following commonly used agents: azathioprine, allopurinol, amidopyrine, aminocaproic acid, ampicillin, aprésoline, aspirin, bactrim, barbiturates, probenecid, phenylbutazone, vasopressin, gentamicin, hydrocortisone, hypothiazid, guanethidine, diacarb, dihydroergotamine, diphenhydramine, desoxycorticosterone acetate (DOCA), ergocalciferol, isoniazid, potassium permanganate, potassium perchlorate, potassium chloride, kanamycin, clofibrate, codeine, cortisone, penicillamine, methazone, 6-mercaptopurine, methyluracil, methyldopa, methicillin, methotrexate, sodium salicylate, neomycin, nitrofurans, novocain, procainamide, paracetamol, PAS, penicillin, pipolfen, pyrabutol, polymyxin B, reserpine, rifampicin, streptomycin, sulfonamides, tetracycline, thyroxine, phenindione, phenobarbital, quinidine, quinine, cephalosporins, and cyclophosphamide.

Drug-induced glomerulonephritis is most frequently caused by azathioprine, codeine, 6-mercaptopurine, sodium salicylate, captopril, novocain, pachycarpine, penicillamine (which can trigger Goodpasture syndrome), gold preparations, rifampicin, sulfonamides, and phenindione.

Nephrotic syndrome frequently occurs with the use of barbiturates, potassium perchlorate, kanamycin, penicillamine, neomycin, PAS, penicillin, streptomycin, and sulfonamides.

Interstitial nephritis may develop with the use of aspirin, allopurinol, azathioprine, nitrofurans, NSAIDs, paracetamol, penicillin, polymyxin B, rifampicin, sulfonamides, isoniazid, cimetidine, phenacetin, and furosemide.

Tubulopathies are caused by the effects of azathioprine, amphotericin B, gentamicin, carbenicillin, heavy metal salts, expired tetracycline, and thiopental.

Acute ischemic tubular necrosis can be triggered by antihypertensives, laxatives, diuretics, and NSAIDs; acute toxic tubular necrosis can be caused by aminoglycosides (especially in combination with cephalosporins or furosemide), amphotericin B, iodinated contrast media, paracetamol, cephalosporins, and cisplatin.

Isolated hematuria develops with the use of anticoagulants, isoniazid, PAS, heavy metal salts, sulfonamides, quinine, quinidine, chlorothiazide diuretics, and cytostatics.

Urinary diathesis and renal colic accompany the administration of immunosuppressants (in high doses), sulfonamides, and thyroxine.

Nephrocalcinosis may develop during Treatment with ergocalciferol and thyroxine.

In Conclusion, we emphasize that only thorough (rather than routine, limited to a standard urinalysis) monitoring of renal function—assessing filtration, concentration, excretion, and endocrine Functions during the administration of any drug, especially drug combinations, in patients with comorbid conditions, allergies, or advanced age—can help diagnose Cytology/cytology/16.html">Early stages of drug-induced nephropathy and guide appropriate preventive and therapeutic strategies.