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

Leading Semiotics of Renal Diseases
Acute Kidney Injury

ARF is a clinical and laboratory syndrome characterized by a rapid decline (within hours or days) in essential renal Functions. For ARF to occur, Kidney function must drop by 95% or more. The incidence of this syndrome ranges from 30 to 50 cases per 1 million population annually.

According to H. Oliver et al. (1973), all etiological factors of ARF are divided into two groups: those that directly damage renal structures (toxic factors) and those that affect renal Blood flow (hemodynamic factors).

Among toxic factors, ARF can be triggered by (A.P. Karapata et al., 1984): aniline, antifreeze, alcohol and its surrogates, lysol, BF and Moment glues, carbon tetrachloride, insecticides, pesticides, snake venom, bee venom, mushroom toxin, helminthic invasion, medications (penicillin, Semisynthetic Penicillins, morphocycline, gentamicin, rondomycin, levomycetin, tetracycline, rifampicin, sulfonamides, nitrofuran derivatives, antifungal Antibiotics), derivatives of salicylic acid and pyrazolone, dextrans, anesthetics, Diuretics, oral contraceptives, immunosuppressants, anticoagulants, vitamin D, etc.

ARF may also develop in the course of numerous internal organ diseases (myocardial infarction, dissecting aortic aneurysm, Pulmonary Embolism, hemorrhagic pancreatitis, pancreatic necrosis, toxic hepatitis, toxemias, salmonellosis, malaria), blood disorders (leukemias, thrombocytopenic purpura, autoimmune hemolytic anemia, multiple myeloma), malignancies (lymphosarcoma, Hodgkin's disease, tumor metastases), myorenal syndrome (high-frequency electric injury, Carbon monoxide poisoning, positional compression in comatose states, nontraumatic myoglobinuria, myoglobinuric myositis, prolonged seizures, necrotic myositis, Muscle overexertion), Central Nervous system disorders (traumatic Brain injury, tumors, inflammatory processes, psychotrauma), as well as certain diagnostic and therapeutic Procedures (excretory urography, retrograde pyelography, aortography, cholecystography, renal biopsy, electroconvulsive therapy, paranepric blockade, Hyperbaric Oxygenation).

It is generally accepted to divide ARF into three forms: prerenal (functional), renal (structural), and postrenal (obstructive). According to H.R. Brady et al. (1995), their incidence is 70%, 25%, and 5%, respectively.

In prerenal ARF, renal function is preserved; however, a decrease in circulating blood volume (CBV) leads to a reduction in effective renal blood flow, resulting in azotemia. If hemodynamic impairment is prolonged, prerenal ARF can progress to renal ARF. Prerenal ARF is subdivided into 4 subgroups (S.I. Ryabov, 2000):

- resulting from impaired myocardial contractility due to various causes;

- reduction in CBV (blood loss, diarrhea, vomiting, massive Burns);

- systemic vasodilation (Sepsis);

- renal vasoconstriction (sepsis, medication use, renal artery stenosis).

In postrenal ARF, Renal Dysfunction occurs As a result of bilateral obstructions to the normal passage of urine from the Kidneys, or obstructions at the level of the bladder or Urethra of a mechanical nature (ureteral stones, tumors, retroperitoneal fibrosis, Prostatic Adenoma, inflammatory edema) or functional nature (brain disorders, Pregnancy, postoperative paresis, use of antispasmodics and ganglion blockers). This form also includes intrarenal ARF caused by acute urate nephropathy (Gout, use of chemotherapeutic agents in patients with myelo- and lymphoproliferative disorders, etc.).

The main causes of renal ARF are kidney diseases (acute Glomerulonephritis, acute Pyelonephritis, exacerbation of Chronic Glomerulonephritis, acute tubulointerstitial nephritis, Renal Amyloidosis, primary nephrosclerosis, Collagen nephropathies, hemorrhagic fever with renal syndrome, Preeclampsia, gouty nephropathy), leptospirosis, rhabdomyolysis, papillary necrosis, vascular processes (renal artery embolism and thrombosis), tubular blockage by sulfonamide crystals or radiocontrast agents, and the effects of endo- or exogenous nephrotoxins.

The primary pathogenetic mechanism of prerenal ARF is renal ischemia. In Shock (hypovolemic, cardiogenic, septic, traumatic), systemic hemodynamic disturbances are accompanied by a drop in renal perfusion pressure, spasm of preglomerular arterioles with Impaired blood supply to the renal cortex, and a decline in GFR.

In the initial phase of ARF, the constrictive action of catecholamines, vasopressin, and renin—released in response to glomerular ischemia (H. Brady et al., 1995)—is counterbalanced by the enhanced synthesis of Prostaglandins, kallikrein, and possibly nitric oxide, which prevent a further decrease in glomerular blood supply by dilating afferent arterioles. As constrictive influences intensify, this equilibrium is disrupted, leading to generalized spasm of preglomerular Arteries.

Further deterioration of intrarenal blood flow or the primary Toxic Effect of a substance on the tubular epithelium leads to The Development of acute tubular necrosis: mitochondrial Swelling, vacuolization of the tubular endothelium Cytoplasm, disappearance of The Endoplasmic reticulum, followed by Necrosis of the tubular epithelium, its transformation into a homogeneous mass, and the Filling of the tubular lumen with it (T.J. Burke et al., 1997; P. Baretti et al., 1997). Depending on the cause, ischemic and toxic forms of acute tubular necrosis are distinguished.

The ischemic form differs from prerenal ARF by more pronounced hypoperfusion, which often leads to irreversible Changes in the tubular epithelium and complete loss of renal functions. Three mechanisms play a role in toxic renal injury: intrarenal vasoconstriction, the direct toxic effect of the substance, and tubular lumen obstruction. THE CONTRIBUTION OF each of these factors varies depending on the offending agent. Thus, vasoconstriction is considered the leading mechanism in The Use of cyclosporine and radiocontrast agents; direct toxic effect, in antibiotics and antitumor drugs; and obstruction, in hyperuricemia and multiple myeloma. In clinical practice, the most frequent causes of ischemic acute tubular necrosis are shock, trauma, Crush syndrome, burns, nontraumatic rhabdomyolysis, sepsis, Hemorrhage, and hepatorenal syndrome; while toxic causes include heavy metal salts (mercury, bismuth, gold, chromium, uranium, arsenic), organic Solvents, carbon tetrachloride, insecticides, stain removers, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), radiocontrast agents, anesthetics, and mushroom toxins (A. Cohen et al., 1998).

The Cells of the pars recta of the proximal tubule are the most sensitive to ischemic and toxic injuries, whereas cells of more distal segments remain virtually intact. The main alterations include loss of the brush border, flattening of the epithelium, and widening of the intercellular spaces between epithelial cells in this nephron segment. Desquamated cells, cellular debris, and precipitated Tamm-Horsfall protein form casts in the distal tubules. There is a certain correlation between necrotic changes and the type of toxic agent (F.H. Cohen et al., 1995). These casts obstruct the tubular lumen, thereby increasing intratubular pressure, which may exceed the hydrostatic pressure in the glomerular capillaries (A. Bajati et al., 1989), leading to tubulorexis. In such cases, GFR ceases completely, and the tubular contents escape into the interstitium through the damaged endothelium (Scheme 1).

Class="center">

Scheme 1. Pathophysiology of tubular necrosis (according to J.A. Shayman, 1999).

The interstitial reaction manifests as The formation of infiltrates composed of lymphoid cells and eosinophils, which is most characteristic of acute tubulointerstitial nephritis of drug-induced or allergic origin.

Necrosis of the tubular epithelium extends to the basement membrane. In most cases, the membrane itself remains undamaged, serving as the starting point for the regeneration of new cellular structures.

The development of acute tubular necrosis and impaired sodium reabsorption serve as further stimuli for increased renin production and activation of the renin-angiotensin-aldosterone system (RAAS). The end product of the RAAS—angiotensin II (AT-II)—in this situation sustains the spasm of the afferent glomerular arteriole, resulting in the redistribution of renal blood flow, a decrease in intraglomerular pressure, and reduced transcapillary transport of Water and dissolved electrolytes.

In recent years, evidence has emerged that The Effect of constrictive agents (primarily AT-II) on renal Blood Vessels in ARF is mediated by changes in the permeability of Cell membranes to calcium and the accumulation of the latter in the Mitochondria of renal cortical cells.

Overall, calcium is assigned a crucial role in the Pathogenesis of ARF. It should be noted that under normal conditions, a very low concentration of free Calcium Ions is maintained in the Cytosol, resting at 0.05-0.5 µmol, which is approximately 100 times lower than the total calcium content in the cellular fraction where it is bound to calmodulin and phosphate. The greater part of cellular calcium (60-70%) is sequestered in mitochondria, 10-20% is located in the endoplasmic reticulum, and the remainder is found in The Plasma Membrane and its covering glycocalyx.

A sharp increase in the concentration of calcium ions during toxic or ischemic renal injury activates phospholipases, leading to the degradation of cell membrane Phospholipids. Lysophospholipids and free Fatty acids are formed within the membranes, causing severe disruptions in Membrane Functions, particularly their permeability. The intensive influx of calcium into The Cell from the extracellular fluid impairs the mitochondria's ability to sequester calcium; consequently, the intracellular concentration of these ions rises significantly, contributing to lethal cell injury.

Traditionally, the course of ARF is divided into 4 phases: initial, oliguric, diuretic recovery, and convalescence.

The initial phase varies in duration—from a few hours in severe shock states to 6-7 days in poisoning. Clinical symptoms during this phase are driven by the underlying condition. There are no reliable indicators capable of confirming or ruling out the onset of ARF at this stage.

The oliguric phase is the most clinically distinct stage of ARF.

The first sign of this phase is a decrease in urine output (to 300-500 mL/day). The urine appears concentrated and dark, contains high amounts of protein and casts, and has a high specific gravity. Oliguria progresses, turning into anuria within 1-11 days. This phase is characterized by anorexia, vomiting, abdominal distension, adynamia, and drowsiness. Blood changes develop relatively quickly—anemia, accelerated ESR, leukocytosis, lymphocytopenia, hypercreatininemia, and hypoalbuminemia. Water-electrolyte balance disorders are also quite typical: hyperkalemia, hypermagnesemia, hyperphosphatemia, hypersulfatemia, hyponatremia, hypochloremia, and hypocalcemia.

In the Cytology/cytology/16.html">Early stages of this phase, relative and true dehydration may occur (e.g., due to vomiting or diarrhea), which are quickly replaced by hyperhydration. Hyperhydration during the oliguric phase carries the risk of acute left ventricular failure and pulmonary edema. Naturally, in postrenal ARF, the clinical picture also shows other signs, specifically those caused by impaired free urination.

Alterations in electrolyte Homeostasis rapidly lead to the development of short-term metabolic alkalosis, followed by metabolic acidosis resulting from hyperphosphatemia and hypersulfatemia.

Frequent complications of this ARF phase include secondary infections (15–25%) and gastrointestinal bleeding (6–10%).

The duration of the oliguric phase coincides with the onset of tubular epithelial regeneration, which is conventionally divided into structural (7-10 days) and functional (10-20 days) recovery subphases.

It should be noted that in 20-30% of cases, a moderate decrease in daily diuresis is observed—the non-oliguric form of ARF, which is more common in acute tubular necrosis of iatrogenic origin.

The early stage of the diuretic recovery phase begins with a gradual increase in daily urine volume by 100-250 mL/day and a decrease in proteinuria; urine specific gravity becomes low, while the aforementioned electrolyte disturbances, hypercreatininemia, and peripheral blood changes persist. Patients' general condition improves only slightly.

Over time, urine output increases, reaching 2 liters or more (sometimes up to 10) per day. This period corresponds to a clinically significant improvement in the patient's general condition.

Patients who have suffered from ARF are particularly vulnerable to antibiotic-resistant strains of microorganisms—70-80% of such patients contract some form of infection, which serves as the cause of death in the polyuric phase for 25% of them. The duration of the diuretic recovery phase ranges from 15 days to 3-6 months, and full renal function is restored within 6-12 months.

Early Diagnosis of renal and prerenal forms is crucial for the effective management of ARF. At the same time, relying solely on a single parameter—such as diuresis or blood creatinine and urea levels—is a diagnostic error.

Let us point out a few key considerations.

The presence of red blood cell casts in the urinary sediment indicates primary glomerular damage, necrotic tubular epithelium points to ischemic or toxic ARF, and eosinophils and lymphocytes suggest acute interstitial nephritis.

In prerenal ARF, the kidneys respond to reduced perfusion by enhanced sodium and water reabsorption to maintain adequate circulating blood volume (CBV), whereas in postrenal ARF, this ability is lost. Therefore, in prerenal ARF, urinary sodium and chloride levels are decreased (urine osmolality exceeds 450 mOsm/kg of water, urine sodium concentration is below 10 mmol/L), the blood urea nitrogen-to-serum creatinine ratio exceeds 20:1, since renal urea reabsorption is passively coupled with sodium reabsorption (normally 10:1), and the urine-to-serum creatinine ratio exceeds 30:1. In renal ARF, the urine is isosmotic to Blood Plasma (urine osmolality is up to 300 mOsm/kg of water), urine sodium concentration is above 20 mmol/L, and the urine-to-serum creatinine ratio is up to 30:1 (L. E. Brodov, 1993).

The uric acid-to-urine creatinine ratio can also be used to determine the cause of ARF. A ratio greater than 1 indicates that ARF is associated with a pathology accompanied by accelerated Protein Catabolism (e.g., leptospirosis), while a ratio less than 1 points to the toxic impact of external factors on the kidneys. Acute Urinary Tract obstruction presents with the aforementioned prerenal changes, whereas chronic obstruction presents with renal-type changes.