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https://doi.org/10.29013/ESR-21-11.12-13-18
Sobirov Maksud Atabaevich, Deputy Director for Research of the Republican Specialized Scientific-Practical Medical Center of Nephrology and Kidney Transplantation Skosireva Olga Valentinovna, Associate Professor of Tashkent State Institute of Dentistry,
Candidate of Therapeutic Sciences Sultonov Nodir Nazirovich, Head of the scientific department of the Republican Specialized Scientific-Practical Medical Center of Nephrology and Kidney Transplantation Tashpulatova Makhsumakhon Khairullaevna, Tashkent State Institute of Dentistry Assistant of the Department of Therapeutic Management № 2.
Е-mаil: ssht61@mail.ru, tashpulatovamaxsumaxon@gmail.com
DRUG-INDUCED KIDNEY INJURY: FOCUS ON NEPHROPROTECTION
Abstract. The article considers the problem of drug-induced kidney damage, mainly against the background of NSAID therapy. It also describes emerging morphological changes typical for interstitial nephritis. Current approaches to treatment of this pathology with the focus on combined nephroprotective therapy are presented.
Keywords: kidneys, drugs, NSAIDs, tubulointerstitial nephritis, nephroprotection.
Current intensive development of pharmaceu- of the liver. The way of NSAID administration does
tical industry and uncontrolled use of drugs by pa- not matter.
tients have increased the incidence of drug-induced The drugs most commonly causing kidney injury lesions of internal organs, and the digestive and re- are NSAIDs and non-opioid analgesics, antibacterial nal organs n particular. According to V. N. Gromyko agents (primarily aminoglycosides, cephalosporins, and V. S. Pilotovich (2016), nearly 20% of all cases sulphonamides, drugs for TB), ACE inhibitors and of acute kidney injury are drug-induced nephropa- ARA II blockers, diuretics, hypouric agents, anti-thies, while in some cases, 10-11% ofpatients need a diabetic drugs (tablets and insulin preparations), substitution therapy after taking certain medications. statins, antiplatelet agents and anticoagulants, hor-Over half of these cases are older adults with comor- mones (GCs, thyroxine), X-ray contrast agents, rabidity requiring a significant amount of medication diation and chemotherapy, protone pump inhibitors, and evidently have a higher risk of renal damage. monoclonal antibodies, antiviral agents, narcotic The literature proves that in addition to age, the risk drugs [2].
factors for analgesic nephropathy include both the In the vast majority of cases, the nephropatho-
NSAID therapy duration and the total dose as well genic effects of drugs (NSAIDs, fluoroquinolones,
as hypovolemia of various etiologies, and cirrhosis 5-ASA) are manifested as chronic, less frequently
acute TIN. Aminoglycosides, penicillins and cephalosporins can cause acute tubular necrosis and kidney failure, cytostatics may cause tubular obstruction by urates, urolithiasis, and ACE inhibitor can be associated with reduction of filtration due to dilation of glomerular outflow arterioles [3].
Drug-induced nephropathy may be associated with direct tubular or interstitial damage and necrosis of the renal papillae, pre-renal effects of the drug (water and electrolyte deficiency, blood vessel occlusion, increased catabolism), urinary tract obstruction, allergic or immune disorders, and vasculitis [4]. The most urgent nephropathy is drug-induced one (analgesic nephropathy).
Currently over thirty million people worldwide take NSAIDs every day and the pool of patients has increased significantly with the COVID19 pandemic. At the same time kidney injury is often detected at an advanced stage of the process with irreversible anatomical changes requiring hemodialysis sessions [5].
NSAIDs are known to inhibit prostaglandin (PG) synthesis deactivating cyclooxygenase (COX); it leads to relief of inflammation and pain. It was found that PG E2, which is involved in maintaining normal renal blood flow in the glomeruli, potassium and sodium excretion, and release of rennin, is mainly formed in the kidneys. It has been shown that PGs are not stored in cells, they are formed "on demand" by the release of arachidonic acid under the action of various triggers with a vasoconstrictor effect (noradrenaline, angiotensin, vasopressin endo-thelin), which disorders intra-renal hemodynamics. The GH synthesized in this case compensates the vasoconstrictor effects, primarily, that one of norepi-nephrine and angiotensin.
NSAID therapy disturbs the balance in this physiological mechanism towards an increase in vasoconstrictor leukotrienes with a simultaneous reduction ofvasodilator PGs, which worsens blood flow in the kidneys with the development of the organ ischemia. An important role in intra-renal hemodynamics is played by sodium. When it is deficient, the synthesis
of COX-2 increases; it stimulates the formation of PGs activating RAAS with and an increase in sodium and water re-absorption and restoration of homeostasis. This fact should be considered when treating patients being on a low-salt diet.
The most common NSAID-induced nephropathy is acute TIN. The spectrum of patients' complaints is very diverse and uninformative, including dyspeptic syndrome with the development ofhypovolemia, various kinds of dieresis disorder to the point of anuria, edematous syndrome, hypo- or hypertension, allergic reactions, erythrocyturea of various expressiveness. When collecting information for a past medical history, special attention is paid to finding out the fact of a pharmaceuticals and / or dietary supplements administration. Laboratory and instrumental diagnostics of analgesic nephropathy is the same as in acute and chronic TIN. Some diagnostic criteria have been developed, i.e. so-called signs of "big" analgesic syndrome [3]. The big analgesic syndrome criteria are: a daily dose of NSAID administered during a year and longer, signs of kidney lesions revealed by ultrasonic examination or CT (uneven contours and reduction of volume of the kidneys, deposits of calcium salts in the kidney cortex). The "small" analgesic syndrome criteria include the patient's history of any chronic painful syndrome, stomach ulcer, and bad mood of different expressiveness.
The treatment for analgesic nephropathy is a challenge because complete cancellation of NSAID for patients suffering from a chronic painful syndrome, is unreal. Taking into account that the most common lesions of the kidneys occur as acute and chronic TIN, NSAID treatment for nephropathy as a whole, is conducted according to current therapy standards of such a nosology. GCS as alternative drugs are only indicated at a rapid progress ofkidney failure against the background of TIN.
The doctors, whose patients are treated with NSAID, need to consider the risk factors of nephropathy development, conduct monitoring of the kidney condition, and, if necessary, perform the
active combined nephroprotective therapy as early as possible [6].
Nowadays the strategy of the therapy for patients with NSAID-induced nephropathy is based on prevention of development of this complication, i.e. nephroprotection. Application of mizoprostol (a synthetic analogue Pg El) to prevent NSAID-induced nephropathy turned to be inadequate due to its low deposition in the body due to which it does not provide necessary vasodilator effect in the kidneys. Some research on the combined drugs rendering a balanced influence on the level ofvasoconstrict-ing leucotrienes and vasodilating prostaglandins are being conducted. This group of the drugs includes licofelon, simultaneously suppressing activity of COG and 5 LOG (lipoxigenase) and rendering analgetic, antipyretic and anti-aggregant effects. However, the findings on drugs obtained by today are insufficient and further research on their efficiency is necessary [7].
Objective: One of the most important links in the pathogenesis of NSAID nephropathy is endothelial dysfunction with the development of vasoconstriction, which leads to deterioration of renal blood flow, decreased glomerular filtration rate, development of nephrosclerosis and AH [8]. There is convincing evidence of active NO synthesis in endothelial and smooth muscle cells of renal vessels, mesangial and tubule epithelial cells, which plays an important role in the regulation of renal blood flow, renal excretory function, and tubulo-glomerular balance. The depression of NO synthesis in the renal vascular endothelium closely correlates with renal tissue reduction, and the accumulation of glycosyl-ation products with the progression of chronic kidney disease reduces the access of NO to its application points [9]. The effect of NO on renal function is known to develop in the interaction of NO with the renin-angiotensin system of this organ [10; 11].
Materials and research methods: Therefore, the use of L-arginine as donators of NO and a nephroprotector is reasonable. These drugs not
only have a pronounced vasoactive effect on renal vessels but also simultaneously improve blood microcirculation and its rheological properties as well as stimulate detoxification processes and promote ammonia excretion.
Research results and discussion: In addition, nitric oxide donors (L-arginine) in combination with NSAIDs (NO-aspirin, NO-naproxen, NO-diclofenac) are currently considered a good way to level the negative effects of NSAIDs on the kidneys. Vasodilatation with these drugs is realized by neutralizing the vasoconstrictor effect of thromboxane, which blocks the depression of prostacyclin, decreased intrarenal blood flow and decreased GFR.
Recently, pentoxifylline (dimethylxanthine derivative) is considered as a nephroprotector as it has a number of positive impacts on intrarenal hemodynamics that are realized through blocking adenosine receptors and inhibition of platelet aggregation, an increase in erythrocyte flexibility, a decrease in hy-perfibrinogenemia with increases fibrinolysis and reduces blood viscosity; it also improves rheological properties of blood. Simultaneously, pentoxifylline dilates vessels and reduces total peripheral vascular resistance, increases the level of oxygenation in the renal tissue. Some literature data indicate that the combination of pentoxifylline with angioten-sin-converting enzyme inhibitor (ACEI) leads to slower progression of renal dysfunction with a significant reduction in proteinuria in patients with CKD of any etiology, which is considered to be a manifestation of endothelium-protective properties of this drug. A more detailed study found out that the nephroprotective effect of this drug is due to the presence of anti-fibrotic and anti-inflammatory properties, combined with hypoglycemic action by improving glucose utilization (R. M. Perkins et al. 2009). By now, pentoxifylline has demonstrated its good tolerability by CKD patients with a reliable nephroprotective effect and no significant side effects; it offers the opportunities for its widespread use in nephrology [12].
Recent research was focused on theophylline therapy for drug-induced nephropathy. Being an adenosine antagonist, this drug not only dilates peripheral and coronary vessels, but renal ones; it also renders simultaneously a moderate diuretic effect. In addition, it inhibits platelet aggregation. There are data on its ability to prevent contrast-induced nephropathy the mechanisms of development of which are very similar to NSAID-induced nephropathy. It enables application of this drug in cases of drug-induced kidney injury [13].
Acetylcysteine also claims the role of cell protector in nephrology protecting vascular endothelial cells from death due to various adverse factors [14]. It is associated with the antioxidant properties of the drug, which are operating in two ways: through the direct removal of free radicals and, indirectly, through the production of glutathione. An additional important feature of acetylcystenin is its marked antitoxic activity against organic and inorganic compounds. Besides, the drug is a basic antidote in paracetamol overdose: in case of paracetamol poisoning, early application of acetylcysteine stimulates glutathione synthesis by the liver with development of systemic protective effect. Low drug price, ease of use, high safety profile (acetylcysteine is an amino acid derivative) offers prospects for its wide use in treatment of NSAID-induced nephropathy [15; 16; 17].
Recently, the repository of nephroprotective agents was added by glutathione, the most important function of which is neutralization of toxins in the gastrointestinal tract and contribution to excretion of those ones that have already been absorbed and are circulating in the body [18]. The evident antioxidant property of glutathione is associated with the high redox potential of its molecule, which is manifested in the binding of free radicals, products of lipid peroxidation and membrane phospholipids of nucleic acids and their removal from the body in the form of non-toxic conjugates. At the same time, glutathione -S-transferase is known to bind toxic metabolites of drugs and antibiotics. In addition, glutathione has a
restorative effect on other antioxidants (vitamins C and E) and acts as an immunomodulator, taking part in the activation of natural killers (NK-cells) and T-lymphocytes [19].
Ethylmethylhydroxypyridine succinate (the amber salt of methylpyridinol) occupies a central position among antioxidants being an inhibitor of free radical processes with membranoprotective, antihypoxic action improving hemorheology. So, it can be added to the list of nephroprotectors. It was discovered that the molecule of this drug penetrates mitochondria where it exhibits antihypoxic effect (owing to 2-ethyl-6-methyl-3-hydroxypyridine) and antioxidant activity (owing to the succinic acid residue). A combination of the two compounds with the unique properties in the ethylmethylhydroxypyri-dine succinate molecule ensures its high bioavail-ability and ability to influence various target organs, resulting in a wide spectrum of the drug effects and high therapeutic potential. The important position of this drug among antioxidants is determined by its impact on many links of free-radical processes not only in biomembranes but also inside cells, as well as by the absence of pro-oxidant effect common for many other antioxidants [20].
Conclusions:
Methylpyridine hydrochloride, a synthetic oxy-pyridine derivative, has a proven antioxidant effect. This drug activates ATP synthesis and energy-stimulating functions of mitochondria with simultaneous stabilization of erythrocyte membrane and vascular endothelial cells. The angioprotective effect of this drug is manifested by reducing the permeability of the vascular wall; its systemic effects are realized by increasing the levels of cyclic nucleotides in platelets with activation ofblood fibrinolysis activity. The drug's instructions indicate that it is an inhibitor of free radical processes with simultaneous angioprotective and antihypoxic effect, which provides its antioxidant effect with nephroprotection with minimal side effects.
Currently, ^AAS blockers and third-generation calcium antagonists have the most convincing evi-
dence base for drugs with a pronounced nephropro-tective effect. The combination of antihypertensive and nephroprotective effects of these drugs significantly slows the progression of nephrosclerosis in patients with chronic TIN of NSAID-etiology.
The present nephroprotection strategy provides a combined (multidrug) approach by simultaneous addressing different mechanisms of renal failure progress. The basis of this approach, as a rule, are RAAS blockers and, less frequently, calcium antagonists of the third generation, which are produced in various combinations with drugs of different pharmacological groups, nephroprotective effects of which are realized in different ways. Such regi-
mens of NSAID-therapy of TIN etiology, helps increase total nephroprotective effect through drugs action synergy and their pleiotropic properties. All these provide better treatment results delaying renal function reduction resulted in the CKD terminal stage.
Abbreviations
ACE= angiotensin-converting enzymer
AH = arterial hypetention
5-ASA = Aminosalicylic acids.
GCS = glucocorticosteroid
GFR = glomerular filtration rate
NSAID = non-steroid anti-inflammatory drugs
TIN = Tubulointerstitial nephritis
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