The chances of developing AKI after exposure to one or more insults depend on a number of susceptibility factors that vary widely from individual to individual: Recent KDIGO guidelines clearly described the importance of interaction between exposures and susceptibility in the final development of the AKI syndrome [2, 3, 10]. Dehydration or volume depletion, advanced age, female gender, black race, presence of chronic diseases (kidney, heart, lung, liver), diabetes mellitus, cancer, anaemia and poly-transfusion, obesity or cachexia all represent conditions identified as general susceptibility to AKI [10].

Besides these general susceptibility conditions, the presence of a pre-existing kidney disease represents an important factor significantly increasing the risk of developing AKI after an insult. As already remarked before, baseline GFR does not necessarily tell the full story about the anatomical and functional conditions of the kidney because a normal baseline GFR or serum creatinine level can be present despite significant reduction of the functional renal mass [17]. This is due to a remarkable renal functional reserve present in intact kidneys. A patient with intact renal functional reserve may tolerate repeated kidney attacks simply loosing part of the reserve and without clinical evidence of the significant damage. An individual with normal baseline GFR could potentially be at increased risk of AKI due to a loss of reserve. Furthermore, when an episode of AKI is resolved and renal function recovery appears complete by measurement of GFR, this does not necessarily mean that a full restoration of renal mass and reserve has also occurred. Interestingly, the lower the remnant kidney mass, the higher will be the susceptibility to further insults and the higher will be the stress imposed to residual nephrons, resulting in hyper-filtration, sclerosis and progressive kidney disease.

Susceptibility factors are not currently clearly defined and their identification depends on many observational studies on different clinical settings [18]. As a matter of fact, however, such factors represent an insult that may be tolerated by some patients whereas may result in mild to severe AKI in others. For this reason, a careful medical history collection and evaluation should be an indispensable part of the process of risk assessment and AKI diagnosis.

KDIGO recommends to keep monitoring high-risk patients until the risk has subsided [10]. Exact intervals for checking serum creatinine and for which individuals’ urine output should be monitored remain matters of clinical judgment; however, as a general rule, high-risk in patients should have serum creatinine measured at least daily and more frequently after an exposure. The same should be true for tight urine output monitoring.

AKI is a multifactorial syndrome and in most cases one or more exposures can be accounted in its pathogenesis. Haemorrhage, circulatory shock, sepsis, critical illness with one or more organ acutely involved, burns, trauma, cardiac surgery (especially with cardiopulmonary bypass circulation), major non-cardiac surgery, nephrotoxic drugs, radiocontrast agents, poisonous plants and animals all represent possible exposures leading to AKI [10]. The clinical evaluation of exposures in the pathogenesis of AKI includes a careful history and thorough physical examination. Among the most important and preventable exposures, we must consider iatrogenic disorders [19, 20]. In several clinical conditions, drugs required to treat diabetes, oncological diseases, infections, heart failure or fluid overload may affect the delicate balance of a susceptible kidney leading to an acute worsening of organ function. Metformin, normally eliminated by the liver and the kidney, may accumulate if CKD pre-exists, inducing lactic acidosis and AKI. Chemotherapic agents used in solid tumour treatments may induce a tumour lysis syndrome with a sudden increase in circulating uric acid levels potentially toxic for the tubule-interstitial component of the renal parenchyma. Antibiotics may certainly result toxic to the kidney causing interstitial nephritis and tubular dysfunction and contribute to progressive renal insufficiency. The same effect can be induced by contrast media, especially if hyperosmolar dye is utilized for imaging techniques. In all these conditions, a cell cycle arrest may be induced with important tubular-glomerular feedback and a negative impact on glomerular hemodynamics [21]. Patients may already be undergoing treatment with aldosterone blockers or ACE inhibitors or angiotensin receptor blockers (ARB). In such circumstances, the original compensatory mechanism in the kidney is blunted or altered. The maintenance of aldosterone blockers when GFR is reduced below 60 ml/min may lead to secondary hyperkalemia and severe disturbances of the cardiac rhythm. Suspension of ACE inhibitors or ARB may produce an apparent improvement of kidney function due to a blockage of the efferent arteriolar vasodilatation [22]. On the contrary, the use of non-steroidal anti-inflammatory drugs in these conditions may exactly induce the opposite effect [23]. Loop diuretics are another family of medications frequently called into question as far as kidney damage is concerned. Diuretics are a double-sided treatment since they may resolve congestion on one side, but they may worsen renal perfusion and arterial underfilling on the other [24]. Furthermore, it is possible that chronic administration of high-dose loop diuretics may induce drug resistance secondary to substantial histological modifications of Henle loop and decrease of renal function [25].