Biomarkers of persistent renal vulnerability after acute kidney injury recovery

Abstract

Acute kidney injury (AKI) is a risk factor for new AKI episodes, chronic kidney disease, cardiovascular events and death, as renal repair may be deficient and maladaptive, and activate proinflammatory and profibrotic signals. AKI and AKI recovery definitions are based on changes in plasma creatinine, a parameter mostly associated to glomerular filtration, but largely uncoupled from renal tissue damage. The evolution of structural and functional repair has been incompletely described. We thus aimed at identifying subclinical sequelae persisting after recovery from cisplatin-induced AKI in rats. Compared to controls, after plasma creatinine recovery, post-AKI kidneys showed histological alterations and attendant susceptibility to new AKI episodes. Tubular function (assessed by the furosemide stress test, FST) also remained affected. Lingering parenchymal and functional subclinical alterations were paralleled by tapering, but abnormally high levels of urinary albumin, transferrin, insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and, especially, the [TIMP-2]*[IGFBP7] product. As subclinical surrogates of incomplete renal recovery, the FST and the urinary [TIMP-2]*[IGFBP7] product provide two potential diagnostic tools to monitor the sequelae and kidney vulnerability after the apparent recovery from AKI.

Urinary proteomics reveals biological processes related to acute kidney injury in Bothrops atrox envenomings

“…It carries the iron from sites of absorption and heme degradation to sites of storage and utilization [ 67 ]. High levels of urine transferrin were reported on a cisplatin-induced AKI murine model investigating persistent renal vulnerability after AKI [ 68 ]. Additionally, it also has been found in patients’ blister fluids following envenoming by snakes in India, which could be associated with local tissue damage [ 8 , 9 , 69 , 70 ].…”

Diagnosis of Cardiac Surgery-Associated Acute Kidney Injury: State of the Art and Perspectives

“…After a solved AKI episode, i.e., following Cr pl normalization (or return to basal levels), patients are not usually monitored, and subclinical sequelae derived from ongoing or defective repair may pass largely unnoticed [ 51 ] ( Figure 1 ). Subclinical sequelae are clinically relevant because patients with incomplete repair retain higher susceptibility to AKI recurrence [ 52 ], and misrepaired structures may eventually give way to progressive chronification of renal disease. Defective recovery from AKI impacts and causes short- and long-term morbimortality [ 53 ], whereas effective recovery is associated to lower risk of long-term mortality and adverse renal complications [ 53 , 54 ].…”

“…In particular, after the normalization of the standard markers of glomerular filtration and tubular function, persistent histological injury correlates with the renal expression and urinary level of KIM-1 in rats [ 64 ]. Additionally, the response to the FST is not only sensitive to extant subclinical tubular injury, but also correlates with the persistence of a state of increased risk of new episodes of AKI [ 52 ]. Both markers are interesting candidates to be prospectively converted into diagnostic tools for the non-invasive follow-up of renal repair.…”

“…The characteristics of the FST make it an outstanding candidate for the detection of subclinical tubular alterations and, thus, for the diagnosis of predisposition to AKI, including CSA-AKI. Recently standardized to study tubular function integrity in humans [ 130 , 131 ], and more recently in rats [ 52 , 103 ], the FST consists of the measurement of the acute, timed diuretic and kaliuretic response to a single administration of furosemide. This response is dependent on intact secretion of furosemide to the lumen of the proximal tubule from peritubular capillaries, and the binding and inhibition of the NKCC transporter in the loop of Henle [ 132 ].…”

“…Because of the specific kinetic features and NKCC inhibition properties, the FST is a high-sensitivity but low-resolution test that detects subtle alterations in tubular performance, but is less sensitive to distinguishing dysfunctional grade or the tubular segments affected [ 103 ]. Very interestingly, the FST has been indicated to detect subclinical conditions such as predisposition to AKI [ 103 ] and the sequelae persisting beyond Cr pl normalization after AKI [ 52 ], which include a higher risk of additional AKI episodes. This makes the FST a suitable candidate biomarker for the diagnosis of risk of CSA-AKI.…”