AKI-CKD Transition Research Articles

Rodent models of AKI-CKD transition.

Acute kidney injury (AKI) is a contributing factor in the development and progression of chronic kidney disease (CKD). Despite rapid progresses, the mechanism underlying AKI-CKD transition remains largely unclear. Animal models recapitulating this process are crucial to the research of the pathophysiology of AKI-CKD transition and the development of effective therapeutics. In this review, we present the commonly used rodent models of AKI-CKD transition, including bilateral ischemia-reperfusion injury (IRI), unilateral IRI, unilateral IRI with contralateral nephrectomy, multiple episodes of IRI, and repeated treatment of low-dose cisplatin, diphtheria toxin, aristolochic acid, or folic acid. The main merits and pitfalls of these models are also discussed. This review provides helpful information for establishing reliable and clinically relevant models for studying post-AKI development of chronic renal pathologies and the progression to CKD.

Transition from acute kidney injury to chronic kidney disease: a single-centre cohort study.

The incidence of acute kidney injury (AKI) is increasing. AKI is currently recognised as an inducer of chronic kidney disease (CKD) and this is known as the 'AKI-CKD transition'. This study aimed to evaluate the rate of decline in estimated glomerular filtration rate (eGFR) associated with AKI events in individuals with and without pre-existing CKD. Inpatients aged 18-80years were retrospectively enrolled. AKI was diagnosed according to the kidney disease improving global outcomes (KDIGO) criteria using serum creatinine levels. Patients with a history of AKI events were divided into four groups according to eGFR before and after the AKI events. In each group, the eGFR levels after an AKI event were compared to those before the AKI event. Patients were further divided into eight groups according to clinical background based on underlying diseases, medications, and surgical history. We analysed data from 9651 patients with AKI. Not surprisingly, we found that eGFR levels during the first AKI event were significantly lower than levels before the event in each group. Furthermore, eGFR levels after the first AKI event were significantly lower than those before the first AKI event, and the eGFR levels after the second AKI event were significantly lower than those after the first AKI event. These trends were similar in each group irrespective of clinical background. Our study revealed that AKI events can cause a decline in kidney function and, as more AKI events occur, acceleration of this decline.

Adipose-derived mesenchymal stem cells employed exosomes to attenuate AKI-CKD transition through tubular epithelial cell dependent Sox9 activation.

Acute kidney injury (AKI) predisposes patients to an increased risk into progressive chronic kidney disease (CKD), however effective treatments are still elusive. This study aimed to investigate the therapeutic efficacy of human adipose-derived MSCs (hAD-MSCs) in the prevention of AKI-CKD transition, and illuminate the role of Sox9, a vital transcription factor in the development of kidney, in this process. C57BL/6 mice were subjected to unilateral renal ischemia/reperfusion (I/R) with or without hAD-MSC treatment. We found that hAD-MSC treatment upregulated the expression of tubular Sox9, promoted tubular regeneration, attenuated AKI, and mitigated subsequent renal fibrosis. However, these beneficial effects were abolished by a drug inhibiting the release of exosomes from hAD-MSCs. Similarly, Sox9 inhibitors reversed these protective effects. Further, we verified that hAD-MSCs activated tubular Sox9 and prevented TGF-β1-induced transformation of TECs into pro-fibrotic phenotype through exosome shuttling in vitro, but the cells did not inhibit TGF-β1-induced transition of fibroblasts into myofibroblasts. Inhibiting the release of exosomes from hAD-MSCs or the expression of Sox9 in TECs reversed these antifibrotic effects. In conclusion, hAD-MSCs employed exosomes to mitigate AKI-CKD transition through tubular epithelial cell dependent activation of Sox9.

Novel insights into acute kidney injury-chronic kidney disease continuum and the role of renin-angiotensin system.

Acute kidney injury (AKI) is an independent risk factor for chronic kidney disease (CKD). If injury is mild, a repair process can be adaptive and lead to complete renal recovery. However, severe injury will be accompanied by a maladaptive repair which usually leads to nephron loss, fibrosis, vascular rarefaction, and chronic inflammation. Although various mechanisms underlying AKI-CKD transition have been explored, no intervention has been proved effective to block the transition until very recently. A lack of consensus for monitoring renal function and defining renal recovery after AKI should be the reasons for the slow advance in the discovery of a timely pharmacologic treatment to block AKI-CKD transition. Recently, animal studies have shown the activation of renin-angiotensin system (RAS) after AKI. In patients with complete renal recovery after AKI defined as the decrease of serum creatinine level to within 0.3mg/dL above the baseline, administration of RAS inhibitor can prevent the ensuing CKD. In this review, we will discuss the renal recovery after AKI and the mechanisms underlying AKI-CKD transition. We will then highlight the promising effect of RAS inhibitor on CKD prevention in patients with complete renal recovery from AKI based on the recent clinical evidence.

Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression.

The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules recovering from AKI undergo pathologic growth arrest, fail to redifferentiate, and become atrophic. These abnormal tubules exhibit persistent, unregulated, and progressively increasing profibrotic signaling along multiple pathways. Paracrine products derived therefrom perturb normal interactions between peritubular capillary endothelium and pericyte-like fibroblasts, leading to myofibroblast transformation, proliferation, and fibrosis as well as capillary disintegration and rarefaction. Although signals from injured endothelium and inflammatory/immune cells also contribute, tubule injury alone is sufficient to produce the interstitial pathology required for fibrosis. Localized hypoxia produced by microvascular pathology may also prevent tubule recovery. However, fibrosis is not intrinsically progressive, and microvascular pathology develops strictly around damaged tubules; thus, additional deterioration of kidney structure after the transition of AKI to CKD requires new acute injury or other mechanisms of progression. Indeed, experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression. Continued investigation of these pathologic mechanisms should reveal options for preventing renal disease progression after AKI.