Acute renal failure: modern pathophysiology, diagnosis and management

Summary

Acute renal failure (ARF), referred to in the modern literature as acute kidney injury (AKI), is a sudden decrease in kidney function occurring within hours to days, leading to retention of nitrogenous waste products (azotemia). It is characterized by an increase in serum creatinine of ≥0.3 mg/dl within 48 hours, an increase of ≥1.5 times the baseline value within 7 days, or a decrease in urine output below 0.5 ml/kg/h for a period of at least 6 hours according to the KDIGO 2012 criteria, updated in 2026.

This review summarizes the epidemiology, etiology, pathophysiology, diagnostic approach, and current therapeutic strategies in ABD.

1. Introduction and definition

Acute renal failure is a clinical syndrome that can be defined as a sudden decrease in renal function, severe enough to result in retention of nitrogenous waste products, as measured by elevated blood urea nitrogen (BUN) and creatinine levels. Traditional criteria for ARF include a 0.5 mg/dl increase in serum creatinine, a 25% increase, or a 25% decrease in glomerular filtration rate (GFR). However, recent evidence suggests that even a modest 0.3 mg/dl increase in serum creatinine is associated with increased mortality and morbidity, necessitating a revision of the diagnostic criteria.

ABD is pathophysiologically classified into three main categories:

·        Prerenal azotemia – reduced renal blood flow

·        Renal (intrinsic) azotemia – parenchymal kidney diseases

·        Postrenal azotemia – urinary tract obstruction

2. Epidemiology

The incidence of AKI varies considerably depending on the clinical setting. The incidence of AKI is:

·        1% upon admission to hospital

·        2–5% during hospitalization

·        up to 20% of patients in intensive care units

·        4–15% after cardiovascular surgery

In a study of 2,216 medical and surgical patients, AKI developed in 5% of them, with 55% of cases being related to iatrogenic factors—primarily adverse drug reactions and sepsis. In a study of 681 intensive care unit patients with AKI, the mean age was 59.5 years, and the majority had complicated comorbidities: 30% had chronic kidney disease, 37% had coronary artery disease, 29% had diabetes, and 21% had chronic liver disease. Female gender has been identified as an independent risk factor for developing AKI after open-heart surgery.

The incidence of severe AKI in adults in Western countries is approximately 140 per million population per year , with 50–70 per million per year requiring dialysis.

3. Etiology

3.1 Prerenal azotemia

Prerenal azotemia is the most common cause of AKI, accounting for 30–60% of all cases. It occurs when glomerular perfusion is reduced due to:

·        Absolute reduction in effective blood volume (hemorrhage, burns, diarrhea, vomiting, diuretics)

·        Relative decrease in blood volume (heart failure, sepsis, anaphylaxis, liver failure)

·        Arterial occlusion (bilateral thromboembolism)

The kidney has the ability to autoregulate GFR and blood flow through independent regulation of afferent and efferent arteriole tone. In mild to moderate prerenal conditions, renal blood flow and GFR are maintained within normal limits. However, in severe prerenal conditions, when adaptive mechanisms cannot compensate, GFR decreases and BUN and creatinine levels begin to rise.

3.2 Acute tubular necrosis (ATN)

ATN is the most common intrinsic renal disease leading to ARF in hospitalized patients. When prerenal and postrenal causes are excluded, approximately 75% of hospitalized patients with ARF have ATN. Approximately 40–60% of ATN cases occur in the postoperative or traumatic setting.

Causes of OTN include:

·        Ischemia – severe or prolonged prerenal azotemia, postsurgical complications

·        Sepsis – septic syndrome

·        Nephrotoxicity :

o   Exogenous nephrotoxins: antibiotics (aminoglycosides, cephalosporins, amphotericin B), iodinated contrast agents (radiocontrast), chemotherapeutics (cisplatin), solvents (ethylene glycol)

o   Endogenous nephrotoxins: intratubular pigments (hemoglobinuria, myoglobinuria), intratubular proteins (myeloma), intratubular crystals (uric acid, oxalate), tumor lysis syndrome

3.3 Postrenal azotemia

Postrenal azotemia accounts for 1–10% of cases of acute renal failure in the hospital setting. It should be considered in older men, especially if they are taking medications that can impair bladder function. Causes include bladder outlet obstruction, bilateral ureteral obstruction, or ureteral obstruction in a solitary kidney.

4. Pathophysiology

4.1 Pathophysiology of prerenal azotemia

Prerenal ARF occurs when glomerular perfusion is reduced. The kidney maintains GFR by dilating the afferent arteriole and constricting the efferent arteriole, maintaining glomerular intracapillary pressure. In severe prerenal conditions, these mechanisms fail. Renal hypoperfusion, a high BUN/creatinine ratio, and low urine output are characteristic. Antidiuretic hormone levels are elevated, which increases water and urea reabsorption.

4.2 Pathophysiology of acute tubular necrosis

ATN is a clinical syndrome of sudden and prolonged reduction in GFR triggered by an acute ischemic or nephrotoxic event. Proposed pathophysiological mechanisms include:

·        Leakage of glomerular ultrafiltrate from the tubular lumen into the interstitium through damaged tubular cells

·        Obstruction of tubular flow by debris or crystals

·        Decrease in glomerular ultrafiltration coefficient

Important biochemical and cellular changes in cell damage include:

·        Mitochondrial dysfunction

·        Adenosine triphosphate (ATP) depletion

·        Phospholipid degradation

·        Increase in cytosolic free calcium levels

·        Decreased Na⁺,K⁺-ATPase activity

·        Changes in substrate metabolism

·        Lysosomal changes

·        Production of oxygen free radicals

Ischemic renal failure, culminating in renal insufficiency, is a complex physiological process resulting from a mismatch between the delivery of oxygen and nutrients and the energy needs of the nephrons. The most important pathophysiological component may be a decrease in local blood flow to the outer medulla of the kidney. Inflammatory cells are involved in the pathogenesis of renal insufficiency. Endothelial cells also play an important role - when damaged, cells swell, cell adhesion molecules are expressed, leukocytes are activated, and renal injury is potentiated.

Despite the frequent use of the term OTN, tubular necrosis is rarely observed. Cell death can be apoptotic or necrotic. Apoptotic pathways, in which endonucleases play an important role, are regulated by mediators such as oxidants, caspases, and ceramides.

5. Clinical manifestations and diagnosis

5.1 Clinical manifestations

In the hospital setting, AKI is most often recognized when patients present with oliguria, elevated BUN and creatinine levels, or both. Rarely, AKI goes unrecognized until the patient develops symptoms of uremia: fatigue, weakness, nausea, vomiting, loss of appetite, metallic taste in the mouth, itching, confusion, fluid retention.

5.2 History and physical examination

The evaluation should begin with a complete medical history and review of hospital records. Important data include:

·        Previous kidney function

·        Medications (aminoglycosides, NSAIDs, ACE inhibitors, contrast agents)

·        Surgical interventions (cardiac and vascular surgeries)

·        Infection or sepsis

·        Hemodynamic parameters

During the physical examination:

·        Reduced body weight, orthostatic hypotension, tachycardia, lack of jugular venous distension – suggest a decrease in extracellular fluid

·        Distended, painful bladder – indicates lower urinary tract obstruction

·        Fever and rash – may be seen in OIN

·        Livedo reticularis – a diagnostic clue for cholesterol or atheromatous emboli

5.3 Laboratory tests

BUN/creatinine ratio: In prerenal conditions, there is a disproportionate increase in the ratio (>20:1) due to increased salt and water avidity. Other causes of elevated BUN include gastrointestinal bleeding, steroids, hypercatabolism, or a high-protein diet.

Diuresis: ABD is traditionally divided into:

·        Anuric – diuresis <100 ml/day

·        Oliguric – diuresis 100–400 ml/day

·        Neooliguric – diuresis >400 ml/day

A normal diuresis with a rising creatinine most often indicates ATN, since prerenal azotemia should result in oliguria. Complete anuria suggests obstruction or an acute vascular event.

Urinalysis and sediment:

·        In prerenal insufficiency: moderate amount of hyaline and finely granular casts

·        In OTN: characteristic sediment in 70–80% of patients – dirty-brown, large granular casts, free renal tubular epithelial cells, and epithelial cell casts

·        In obstruction: seemingly benign sedimentation with few formed elements

·        In proliferative glomerulonephritis: 3+ to 4+ protein, 2+ to 3+ blood, activated sediment with erythrocytes and erythrocyte casts

·        In rhabdomyolysis: heme-positive urine without erythrocytes, elevated CPK, myoglobinuria

·        In OIN: leukocytes in clumps and in cylinders, eosinophilia in urine

Urinary indices: Often used to differentiate prerenal azotemia from OTN:

Table

Fractional urea excretion (FEUrea) may also be useful, especially in patients taking diuretics.

5.4 Imaging studies

Renal ultrasonography is the first choice in AKI because it is noninvasive and reliable. Normally large kidneys in advanced azotemia usually suggest acute rather than chronic renal failure. Ultrasound is useful for confirming or ruling out obstruction, identifying polycystic kidney disease, and locating the kidney for biopsy.

High-resolution CT is considered the scan of choice if urolithiasis is suspected. Magnetic resonance angiography is recommended for the evaluation of renal arterial or venous thrombosis.

5.5 Kidney biopsy

Renal biopsy is rarely necessary in hospital-acquired AKI. It is indicated in cases of unclear etiology, when the clinical picture suggests other possibilities (obstruction, vascular incident), in cases of complete anuria, or in cases of persistent oliguria for more than 4 weeks.

6. Specific causes of acute renal failure

6.1 Radiocontrast-induced nephropathy

Radiocontrast is a common cause of AKI. In patients with normal renal function and no other risk factors, the incidence is low (<1%). The most important risk factor is previous renal failure; others include diabetes, dehydration, advanced age, heart failure, high total dose of contrast, and concomitant exposure to other nephrotoxins.

A meta-analysis of 31 controlled trials with over 5,000 patients compared high-osmolar with low-osmolar agents; all but nine studies reported a favorable outcome for patients receiving low-osmolar agents. Iodixanol, a nonionic, isoosmolar contrast medium, has shown benefit in high-risk patients.

Prevention includes:

·        Hydration with saline 1 ml/kg/h for 8–12 hours before and after the procedure

·        Limiting the volume contrast

·        Use of iodixanol in high-risk patients

·        Acetylcysteine 600 mg orally twice daily the day before and on the day of the procedure (conflicting data)

·        Hydration with sodium bicarbonate before contrast – more effective than sodium chloride

6.2 Aminoglycosides

The most important manifestation of aminoglycoside nephrotoxicity is AKI secondary to ATN, occurring in 10–20% of patients. It is usually mild and nonoliguric, with an increase in serum creatinine after about 1 week of therapy. Patients may develop polyuria and hypomagnesemia.

Risk factors for potentiating nephrotoxicity include renal ischemia, aminoglycoside dosing regimen and serum levels, sepsis, other nephrotoxins, and liver disease. Once-daily dosing is as effective in controlling infection as more frequent dosing, with less nephrotoxic effect.

6.3 Amphotericin B

Amphotericin B is a relatively common cause of AKI. Hydration with saline prior to infusion reduces the incidence of AKI. Amphotericin B in lipid emulsion may be less nephrotoxic.

6.4 Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are potent inhibitors of prostaglandin synthesis, which contributes to their nephrotoxicity in high-risk patients who require prostaglandins to maintain renal vasodilation. The most common pattern of injury is prerenal azotemia. NSAIDs have also been associated with the development of acute renal failure, which is often accompanied by renal failure and marked proteinuria.

6.5 Cisplatin

Renal impairment is a well-known complication of cisplatin. 25–35% develop a mild and reversible decrease in GFR after the first dose. With subsequent doses, the incidence and severity of renal failure increase. Hypomagnesemia can be severe and occurs in 50% of patients.

6.6 Ethylene glycol

Ethylene glycol produces a syndrome of severe metabolic acidosis with a high anion gap and a large osmolar gap. Key clinical findings include initial disorientation and agitation, progressing to CNS depression, renal failure, metabolic acidosis, respiratory failure, and circulatory failure. Calcium oxalate crystals are typically found in the urinary sediment.

Treatment includes intravenous infusion of sodium bicarbonate, ethanol, or fomepizole to block ethylene glycol metabolism, and hemodialysis to remove ethylene glycol and glycolate.

6.7 Rhabdomyolysis

The most common causes are trauma, ischemia, excessive muscle activity, metabolic disorders, drugs, and infections. Important diagnostic clues are muscle pain and dark brown urine, positive for blood on dipstick but no red blood cells. The diagnosis is confirmed by elevated CPK and myoglobin levels.

Approximately one-third of patients with rhabdomyolysis develop AKI. Early recognition and initiation of treatment are key. The most important aspect of management is rapid volume replacement with saline solution at 200–300 ml/h. Alkalinization of the urine with sodium bicarbonate may protect the kidney from myoglobin and urate nephrotoxicity.

6.8 Hyperuricemic acute renal failure (tumor lysis syndrome)

Occurs in malignant diseases with a high rate of tumor cell turnover. Prevention includes:

·        Hydration and forced diuresis to maintain diuresis >3–5 L/24h

·        Alkalinization of urine (pH >7)

·        Allopurinol 300–600 mg/day, starting 3 days before chemotherapy

·        Rasburicase (recombinant urate oxidase) – more effective and faster than allopurinol

6.9 Hepatorenal syndrome (HRS)

HRS is defined as renal failure in patients with severely compromised liver function in the absence of other known causes. It closely resembles prerenal failure but does not respond to conventional volume replacement. The etiology involves a significant reduction in renal perfusion associated with splanchnic vasodilation.

In patients with cirrhosis and ascites, the probability of developing HRS is 18% at 1 year and 39% at 5 years. Treatment is conservative; specific agents include octreotide, midodrine, albumin, and terlipressin. The prognosis is poor unless liver function can be improved—usually by liver transplantation.

7. Management of acute renal failure

7.1 Prevention

Prevention is the cornerstone of management. Approximately 25% of all hospital-acquired AKI cases are associated with the use of one or more nephrotoxic agents. Strategies include:

·        Identification of patients with risk factors (age, impaired renal function, diabetes, dehydration)

·        Avoidance of nephrotoxic agents

·        Applying preventive strategies in specific circumstances

7.2 Maintenance therapy

Because OTN is inherently a catabolic disorder, patients lose about 0.5 lb (0.23 kg) per day. Providing adequate calories (1,800–2,500 kcal or 35 kcal/kg/day) and protein (1.0–1.4 g/kg/day) is important. The use of hyperalimentation with 50% dextrose and essential amino acids has little effect on reducing mortality.

7.3 Dialysis

Indications for initiating dialysis include:

1.      Severe hyperkalemia, acidosis not readily controlled by medical treatment, or both

2.      Volume overload unresponsive to fluid restriction, diuretics, or both

3.      Signs or symptoms of uremia (pericardial friction rub, asterixis, mental status changes, seizures)

In the absence of these indications, most nephrologists recommend dialysis when the BUN reaches 80–100 mg/dl, in order to avoid uremic symptoms. Continuous renal replacement therapy (CRRT) is the preferred approach in critically ill patients who are intolerant to hemodialysis due to hypotension.

7.4 Treatment of complications

Hyperkalemia: A life-threatening complication that often requires emergency intervention. Consistent ECG changes include peaked T waves, PR interval prolongation, QRS complex widening, and sinusoidal pattern. Treatment is initiated with calcium chloride or calcium gluconate for immediate stabilization of the cardiac membrane. Insulin and glucose, inhaled beta-agonists, or sodium bicarbonate help redistribute potassium into the intracellular space. Sodium polystyrene sulfonate (oral or enema) or dialysis is used to remove potassium from the body.

Volume overload: Loop diuretics are the most useful therapy. Furosemide can be administered intravenously as a bolus or by continuous infusion. The main risk of high doses of furosemide is deafness, which may be transient or permanent.

Hyponatremia: Usually associated with hypervolemia. Initial management is with loop diuretics and free water restriction. Correction should be gradual, with a target sodium increase of 1–2 mEq/L/h until symptoms resolve or serum sodium reaches 120 mEq/L.

Metabolic acidosis: If pH >7.2, it can be treated with oral sodium bicarbonate. In severe metabolic acidosis with pH ≤7.1, intravenous sodium bicarbonate and/or renal replacement therapy is administered.

Anemia: Normochromic-normocytic anemia develops in 65–95% of patients with AKI. Hemoglobin should be maintained above 10 g/L. Erythropoietin is increasingly used to reverse anemia and reduce the need for blood transfusions.

8. Forecast

Mortality can reach 50–80% in patients with AKI in association with sepsis, hypotension, and respiratory failure. The prognosis depends on the clinical setting, comorbidities, the underlying cause of the renal failure, its severity, and how early the diagnosis is made and treatment is initiated.

In patients who survive the acute episode, renal function essentially returns to normal, except for a possible defect in the kidney's concentrating ability. However, a growing body of evidence suggests that a significant percentage of patients with ATN do not recover their renal function and may require long-term dialysis.

9. Conclusion

Acute renal failure remains a serious clinical problem with high mortality, especially in critically ill patients. Despite significant advances in dialysis and intensive care, mortality in patients with severe ARF requiring dialysis has not decreased significantly over the past 50 years. Therefore, prevention and early diagnosis remain the cornerstones of management. Discovery of biomarkers that can predict the development of renal dysfunction before serum creatinine increases may lead to early and successful treatment. The current KDIGO 2026 guidelines emphasize the importance of multicomponent strategies for kidney protection, nephrotoxic stewardship, and coordinated follow-up of patients after an episode of ARF to reduce the risk of chronic kidney disease.

Literature

1.     Liano F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int. 1996;50:811.

2.      Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int. 2004;66:1613.

3.      KDIGO 2026 Clinical Practice Guideline for Acute Kidney Injury (AKI) and Acute Kidney Disease (AKD). Public Review Draft, March 2026.

4.      Shaver MJ, Shah SV. Acute Renal Failure. ACP Medicine, Nephrology VI. WebMD, Inc. 2005.

5.      Kellum JA, Lameire N, Aspelin P, et al. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1-138.