Address For Correspondence:
R Bhimma, Department of Paediatrics & Child Health, Nelson R Mandela School of Medicine, University of Kwazulu-Natal, Private Bag 7, Congella, 4013, South Africa.
Email: bhimma@ukzn.ac.za


AKI may develop in 3 clinical patterns: (1) as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons; (2) in response to cytotoxic, ischemic or inflammatory insults to the kidney, with structural and functional damage; and (3) with obstruction to the passage of urine.

Pre-renal injury is reversible once blood volume and hemodynamic conditions have been restored. Failure to do this can result in intrinsic AKI due to hypoxic/ischemic acute tubular necrosis (ATN). When renal perfusion is compromised, the afferent arterioles relax their vascular tone to decrease renal vascular resistance and maintain renal blood flow. Intra-renal generation of vasodilatory prostaglandins including prostacyclin mediates vasodilatation of the renal microvasculature to maintain renal perfusion. Administration of cyclo-oxygenase inhibitors such as aspirin or non-steroidal anti-inflammatory drugs can inhibit this compensatory mechanism and precipitate AKI [19]. During pre-renal injury the tubules respond to decreased renal perfusion by appropriately conserving sodium and water such that the urine osmolality is greater than 400-500 mosmol/l, urine sodium is less than 10-20Eq/l and the fractional excretion of sodium is less than 1%. In newborns and premature infants, the relative immaturity of the renal tubules need to be taken into account. Thus corresponding values are a urine osmolality greater than 350 mosmol/l, urine sodium less than 20-30mEq/l and fractional sodium excretion of less than 2.5% [20,21]. The use of these values to differentiate pre-renal injury from ATN requires that the patient have normal tubular function initially. However, newborns with immature tubules and children with pre-existing renal disease or salt-wasting adrenal disease, as well as other diseases might have urinary indices suggestive of ATN but in fact have pre-renal failure. In addition, the fractional excretion of sodium may be falsely increased in patients receiving diuretic therapy [3].

In children with intrinsic renal disease due to hypoxic/ischemic AKI, there is early vasoconstriction followed by patchy tubular necrosis. The exact mechanism of cellular injury in this condition is unknown but the following are thought to play a role: alterations in endothelin or nitric oxide regulation of vascular tone, ATP depletion and alterations in the cytoskeleton, changes in heat shock proteins, inhibition of the inflammatory response and the generation of reactive oxygen and nitrogen molecules [22,23]. In children with multi-organ failure, the systemic inflammatory response is thought to contribute to AKI as well as other organ dysfunction by the activation of the inflammatory response, including increased production of cytokines and reactive oxygen molecules, activation of polymorpho-nuclear leukocytes and increased expression of leukocyte adhesion molecules [24].

Nephrotoxic AKI from medications is at least in part due to toxic tubular injury. Aminoglycoside nephrotoxicity typically presents with non-oliguric AKI, with urinalysis showing minimal urinary abnormalities. Factors influencing the development of AKI from amino-glycoside use include the dose and duration of therapy as well as the level of renal function prior to the commencement of treatment. There is disruption of lysosomal function in the proximal tubular and this is reversible once the amino-glycoside has been discontinued. However the serum creatinine may continue to increase for several days due to ongoing tubular injury from continued high parenchymal levels of the aminoglycoside [3]. Other common agents include intravascular contrast, Amphotericin B, chemotherapeutic agents such as ifostamide and cisplatin, acyclovir and acetaminophen.

Table 5 illustrates a classification of various drugs known to cause AKI based on pathophysiological mechanisms [25]. Table 6 illustrates a list of common biological nephrotoxic produced by animals that cause AKI [26].

Table 5: Classification of various drugs based on pathophysiological categories of acute kidney injury

Pathophysiology	Drugs known to cause acute kidney injury.
Prerenal failure	Non-steroid anti-inflammatory drugs, angiotensin converting enzyme, cyclosporine A, norepinephrine, antiogensin-2 receptor antagonists, diuretics, interleukins, cocaine, mitomycin C, tacrolimus, estrogen, quinine.
Acute tubular	Antibiotics: aminoglycosides, cephalosporins, Amphotericin B, rifampicin, vancomycin, foscarnet, pentamidine, Non-steroid anti-inflammatory drugs, glaphenin, contrast media, acetaminophen, cyclosporine A, cisplatin, IV immunoglobulin, dextran, maltose, sucrose, mannitol, heavy metals
Acute interstitial nephritis	Antibiotics: ciprofloxacin, methicillin, penicillin G, ampicillin, cephalosporins,oxacillins, rifampicin. Non-steroid anti-inflammatory, glaphenin, acetylsalicylic acid (ASA), fenoprofen, naproxen, phenylbutazone, piroxicam, tolmetin, zomepirac, contrast media, sulphonamides, thiazides, phenytoin, furosemide, allopurinol, cimetidine, omeprazole, phenindione, zomepirac
Tubular obstruction	Sulfonamides, methotrexate, methoxyflurane, glaphenin, triamterene, acyclovir, ethylene glycol, protease inhibitors
Hypersensitivity angitis	Penicillin G, ampicillin, sulphonamides
Thrombotic microangiopathy	Mitomycin C, cyclosporine A, oral contraceptives

Adapted with permission from reference [1].

Table 6: Common biological nephrotoxics produced by animals

Animal	Biologic nephrotoxins
Snake	Phospholipase A2, myotoxins, Procoagulant-activating factors V and X
Spider	Sphingomyelinase D, neurotoxins
Bee	Melittin, phospholipase A2, Mast-cell Degranulation protein
Wasp	Antigen 5, Mastroparans
Murines animal (carp, jellyfish, sea anemone)	Ichthyogallotoxin, cyprinol

Modified by Chisney and Jones [Reproduced with permission from 1].

Children with AKI caused by nephrotoxic agents have a significant risk for development of chronic kidney disease. Although drugs are an infrequent cause of AKI in children in the general population, drugs and hypoxia are the leading cause of hospital-acquired AKI, with significant morbidity and mortality. The judicious use of nephrotoxic drugs and their combinations, together with adequate hydration, are still the most important measures to take in minimising nephrotoxicity.

Haemolysis and rhabdomyolysis from any cause can result in sufficient hemoglobinuria or myoglobinuria to induce tubular injury and precipitate AKI. The mechanisms of AKI are complex but may be related to vasodilation, precipitation of the pigments in the tubular lumen and/or heme-protein-included oxidant stress [27].

Uric acid nephropathy and tumour lysis syndrome are most common in children with acute lymphocytic leukaemia and B-cell lymphoma [39]. The pathogenesis of uric acid nephropathy is complex but a potentially important mechanism of injury is related to the precipitation of crystals in the renal tubules leading to obstruction of urine flow and in the renal microvasculature, obstructing urinary blood flow severely [39,40]. AKI during tumour lysis syndrome can also result from extreme hyperphosphataemia from rapid breakdown of tumour cells and the precipitation of calcium phosphate crystals [28].

In children with AKI due to acute interstitial nephritis, the clinical features include rash, fever, arthralgias, eosinophilia and pyuria with or without eosinophiluria. Acute interstitial nephritis is most often due to a reaction to a drug but may be idiopathic. Withdrawal of the offending agent together with corticosteroid therapy may aid in improving renal function.

Any form of glomerulonephritis including rapidly progressive glomerulonephritis can progress to AKI. Whilst post-infectious glomerulonephritides are less likely to progress to chronic kidney disease, the other forms of glomerulonephritis presenting with AKI may progress to chronic kidney disease, with or without treatment. Clinical features include hypertension, oedema, haematuria, and a rapidly using blood urea nitrogen and serum creatinine. Since therapy is largely dependent on biopsy findings in rapidly progressive glomerulonephritis, a biopsy should be performed early in the course of the disease [3].

Cortical necrosis as a cause of AKI is most common in neonates and presents with microscopic haematuria, oliguria, hypertension and elevated levels of blood urea nitrogen and creatinine. Thrombocytopenia may also be present due to microvascular injury. As the disease progresses, ultrasound may show decreased kidney size due to atrophy. Children with cortical necrosis may partially recover or not at all. Haemolytic uremic syndrome in older children may lead to cortical necrosis with substantial morbidity and mortality [29].

Post renal AKI arising from obstruction of the urinary tract occurs if there is obstruction in a solitary kidney, if it involves the ureters bilaterally, or if there is urethral obstruction. In unilateral obstruction, the rise in serum creatinine levels may not be apparent due to intact contralateral renal function. Although the serum creatinine may remain low with unilateral obstruction, significant loss of glomerular filtration occurs and patients develop progressive loss of glomerular filtration if the obstruction is not relieved [3]. Patients who develop anuria typically have obstruction at the level of the bladder or downstream to it.