Aetiology
Often complex, with more than one mechanism at play. Most common causes can be grouped as follows:[5][10]
Ischaemia
Systemic hypoperfusion: caused by dehydration (e.g., severe diarrhoea and vomiting), bleeding, extensive burns, trauma, cardiac surgery, overwhelming sepsis, or major surgery.
Local hypoperfusion: caused by cold ischaemia during renal transplantation, renal surgery, renal artery thrombosis, cardiac surgery, or aortic dissection.
The sensitivity of individual patients to a decrease in renal perfusion is variable. For example, some patients suffer from ATN after a few minutes of hypoperfusion while others tolerate several hours of ischaemia without structural damage to the kidney.
Exogenous toxins
Many drugs and poisons can cause ATN. In general, nephrotoxins cause renal injury by inducing a varying combination of intrarenal vasoconstriction, direct tubular toxicity, and/or tubular obstruction. Examples include: aminoglycosides, amphotericin-B, poisons (e.g., ethylene glycol), chemotherapeutic agents (e.g., cisplatin), non-steroidal anti-inflammatory drugs, radiocontrast media, or bacterial toxins.
The nephrotoxic potential of most agents is dramatically increased in the presence of borderline or overt ischaemia, sepsis, or other renal insults.
Endogenous toxins
These include increased haem (from myoglobin release as in rhabdomyolysis, or increased haemoglobin release as in haemolysis), increased uric acid (e.g., gout, lysis syndrome), or increased light chain proteins (e.g., myeloma kidney).
Pathophysiology
While the exact pathogenesis of ATN is unknown, many possible mechanisms have been studied.
The kidney is an extremely vascular organ, receiving 20-25% of the cardiac output. Renal blood flow is distributed selectively; blood flow to the outer cortex is higher (up to 90%) compared with the outer and inner medulla, as most of the blood perfusion is directed on glomerular filtration. This vascular architecture generates a gradient of decreasing oxygen that results in a state of relative hypoxia within the renal medulla, where part of the tubular system is located, which is more sensitive to ischaemic insults. In addition, the proximal tubule has a high oxygen requirement, as it is responsible for the reabsorption of sodium and transport of glucose, amino acids, and other solutes.[11][12]
Following a situation of hypoperfusion or nephrotoxicity, epithelial cells are unable to keep an adequate intracellular adenosine triphosphate (ATP) for essential processes. This reduction of ATP leads to cell injury, and if severe enough, apoptosis with detachment of the basement membrane. This results in proximal tubular dilatation and formation of distal tubule cast, which can obstruct the tubule lumen.[12] Proximal tubular cell injury and dysfunction also causes vasoconstriction mediated by tubuloglomerular feedback, renin-angiotensin-aldosterone, or endothelin. Tubular damage itself can be associated with a decline in glomerular filtration rate (GFR). However, this damage usually affects sodium reabsorption in the proximal tubule, resulting in a high sodium concentration in the filtrate reaching the distal tubule, stimulating the macula densa mediating afferent arteriolar vasoconstriction.[12]
Damage to the endothelial cells triggers an immune response, with recruitment of leucocytes, release of chemokines (e.g., tumor necrosis factor alpha, interleukin 1), cytokines, and other soluble mediators that contribute to the pathogenesis.[12]
Clinical course
The sequence of disease progression in ATN can be divided into four steps:[10]
Initiation phase: the injury to tubular epithelial cells caused by ischaemia or nephrotoxins is evolving but not yet established. As the dysfunction progresses, there is a depletion of ATP which leads to cell death and detachment from the basement membrane, causing tubular necrosis that reduces blood volume and renal perfusion. Immediately after endothelial or epithelial cell damage, an immune response is triggered, leading to recruitment of inflammatory cells and generation of oxidative stress. There is an acute decrease in GFR to low levels, with a sudden increase in serum creatinine and blood urea nitrogen concentrations. ATN is potentially preventable during this period.
Extension phase: In this phase, early diagnosis and treatment play a key role. The two major events that occur in this phase, occurring mainly in the corticomedullary junction, include continued hypoxia and the inflammatory response. Cell injury continues and apoptosis or necrosis may be present, mainly in the outer medulla, leading to a continuous fall in the GFR. Blood flow returns to normal levels in the proximal tubule cells of the cortex, which starts to undergo cellular repair. There is continuous production and release of chemokines and cytokines that amplify the inflammatory response. Interrupting this inflammatory response could have therapeutic implications. Due to the reduction in GFR, creatinine and urea continue to rise and oliguria may be present. Reduction in the ability of the nephrons to eliminate waste results in azotaemia, fluid retention, electrolyte imbalance, and metabolic acidosis.
Maintenance phase: renal injury is established. Cells undergo repair, migration, apoptosis, and proliferation in order to try to re-establish cellular and tubular integrity. Endothelial cell necrosis and sloughing lead to tubular obstruction and increased tubular permeability. GFR reaches a stable nadir. This phase may last from several days to months and will determine the prognosis. Oliguria and a prolonged maintenance phase are signs of poor renal prognosis.
Recovery phase: patients recover renal function through repair and regeneration of renal tissue. There is cellular differentiation, epithelial polarity is re-established, and normal cellular function starts to return. Growth factors are released that aid in repair by promoting the proliferation of renal tubular cells. Tubular function is restored, and is characterised by an increase in urine output (if oliguria was present during the maintenance phase) and by a gradual decrease in urea and serum creatinine to their pre-insult levels.
Classification
Types of ATN[5]
Ischaemic:
Caused by systemic or renal hypoperfusion.
Nephrotoxic:
Caused by drugs, poisons, radiocontrast media, or endotoxins.
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