INTRODUCTION
The traditional view of kidney repair was based on the concept that the glomerulus does not have regenerative capacity and responds to injury with hypertrophy [1], while the tubule has an extended regenerative capacity and responds to tubular cell loss by dedifferentiation and proliferation of survived tubular cells [2]. The identification of renal progenitors, a population of kidney cells localized within the Bowman’s capsule and scattered among tubular epithelial cells with self-renewal capacity and the capacity to differentiate into multiple types of tubular cells as well as in podocytes [3] has revised our understanding of kidney repair [4].
GLOMERULAR REPAIR
A crucial problem in glomerular repair is replacement of lost podocytes [5]. Podocyte loss, observed in most kidney diseases, correlates with chronic kidney disease (CKD) [5]. Podocytes are highly differentiated post-mitotic cells that cannot undergo cell division; rather, pushing them across mitosis can trigger detachment or death by catastrophic mitosis [6]. When podocyte loss happens, two main responses occur: hypertrophy of survived podocytes, which increases their size and function to quickly compensate the podocyte loss [5], and second, renal progenitors migrate towards the glomerular tuft and differentiate into podocytes, replacing lost ones [7, 8]. If the process is successful, the glomerulus restores its function and structure with complete healing [9]. If the process is perturbed and renal progenitor differentiation into podocytes is not successful, the renal progenitors migrate towards the tuft without having achieved podocyte features that cannot interdigitate, generating hyperplastic glomerular lesions [10], accumulating extracellular matrix and turning into glomerular scars, referred to as focal segmental glomerulosclerosis lesions. An overshooting renal progenitor hyperplasia can also happen, generating crescentic lesions [11].
TUBULAR REPAIR
Our understanding of tubular damage and its relationship with kidney function loss evolved by World War I [12]. At that time, dialysis did not exist and the risk of dying of acute kidney injury (AKI) was extremely high [12]. However, the clinical experience was that patients who survived the acute phase of the injury frequently recovered kidney function and, in the kidney tissue, this associated with a phase of restoration of tubular epithelium integrity after a phase of widespread necrosis [12]. The regenerated tubular epithelium appeared first as poorly differentiated and later was taking again the phenotype of fully differentiated tubular cells [12–14]. The substantial clinical reversibility of AKI related to a high proliferative capacity of the tubular epithelium was apparently corroborated by widespread positivity of tubular epithelial cells for cell cycle markers such as Ki67, PCNA and BrdU used to label tissues from animal models to mirror proliferation [13–15]. Immunostaining for these markers was also observed in human kidney biopsies of patients with AKI [14, 16], but time course analyses are not available due to the lack of follow-up kidney biopsies in patients with improving kidney function. The general concept of the pathophysiology of AKI remained substantially unchanged until recently, because it apparently fitted the clinical experience that a patient who survived AKI could recover kidney function and be discharged from the hospital in seemingly good condition.
But what is the clinical experience that we have of patients with AKI? Dialysis and the constant improvement of patient management in intensive care units improved lethality of AKI in the acute phase. The fact that many more patients with even severe forms of AKI survive the acute phase enabled a view of the long-term consequences of AKI, e.g. CKD and an increased cardiovascular mortality even after discharge from the hospital with recovered kidney function [17]. Epidemiological data suggest that the risk of developing CKD after an AKI is proportional to the severity of the AKI episode [18]. This questions the idea of a generally high regenerative potential that is not achieved in a subset of patients because of a maladaptive response, and rather suggests irreversible nephron loss and a more general problem of incomplete regenerative response to AKI. Recent results support this concept, showing that regeneration after AKI is limited and mostly ascribed to renal progenitors, while differentiated tubular cells undergo hypertrophy to promptly recover kidney function [19]. Surviving tubular epithelial cells increase their working capacity by undergoing an alternative cell cycle called endoreplication [19]. This process allows differentiated tubular cells, particularly in non-injured S2 segments, a compensatory hypertrophy to take over the filtration load of non-functioning injured or lost nephrons [19]. This leads to a quick recovery of kidney function and saves the patient’s life, while tubular progenitors proliferate to drive regeneration in necrotic S3 tubular segments of affected nephrons [19]. This explains the widespread positivity for cell cycle markers in S2 segments, which are not even directly injured during AKI [19].
Meanwhile, a second response occurs, i.e. proliferation of renal progenitors that replace lost tubular cells and reconstitute, at least in part, tissue integrity [19]. Altogether, this can lead to a partial or even complete recovery of kidney function. The more severe the injury, the more nephrons get lost and the more differentiated cells have to endocycle to recover kidney function, increasing the risk of developing CKD.
In summary, the kidney behaves similar to the liver and the heart [4]; in response to injury in these essential organs, two responses occur: endoreplication of differentiated parenchymal cells to undergo hypertrophy and increase function by becoming polyploid and proliferation of a subset of resident cells with progenitor features that undergo true proliferation to replace, at least in part, lost cells [4].
TUBULAR REPAIR AND KIDNEY TUMOURS
Recent evidence suggests that CKD development is not the only possible long-term complication of AKI [17]. Patients who survive an AKI episode have an increased risk of death from cardiovascular complications and tumours [17]. In particular, patients with AKI exhibit an increased risk of developing a papillary renal cell carcinoma (RCC) [17, 20]. Papillary RCC represents ∼15% of all the kidney tumour histotypes and is more frequently observed in patients in ESKD and kidney allograft recipients. The mechanistic link between AKI and papillary RCC is represented by renal progenitors. Indeed, papillary RCC is generated by clonal proliferation of renal progenitors that undergo clonal expansion after AKI to provide tissue regeneration [19]. An excessive and dysregulated clonal expansion, promoted by overactivation of crucial repair pathways, such as Notch, leads to tubular hyperproliferation, then adenoma development and finally adenoma transformation into papillary RCC [20]. The possible origin of other types of kidney tumours from renal progenitors suggests that these cells may represent a crucial starting point for neoplastic transformation in the kidney [21–23].
The development of papillary RCC is a process that resembles the development of an adenoma–carcinoma sequence from colon stem cells [24]. This is considered to be a multistep process that starts from an abnormally proliferating epithelium that, upon different steps of genetic and epigenetic alterations, turns into a tumoural growth generating a benign tumour, the adenoma, and then upon accumulation of further hits into malignant transformation [24]. In the case of papillary RCC, this would represent the result of an overshooting response of renal progenitors to AKI turning from hyperproliferation into benign and then malignant tumour development [20]. Autopsy studies report a high prevalence of papillary adenomas in the kidneys of patients ˃50 years of age [25], consistent with the high prevalence of AKI in the aging population and suggesting that development of papillary carcinoma in the kidney is a multihit process where AKI may represent one crucial hit.
Why were the increased risk of CKD and cancer after AKI recognized only recently? Mostly because both the risks are inherently related to our increased capacity to allow patients to survive severe AKI long enough. This gives the transformed renal progenitors the time to expand enough to generate an adenoma and then a carcinoma.
In conclusion, recent evidence revises the traditional concept of how the kidney responds to injury. The glomerulus and the tubule both respond to injury by hypertrophy of the differentiated parenchymal cells and by proliferation of local immature progenitors (Figure 1). These two mechanisms happen at the same time and have to be tightly balanced to optimize overall survival and tissue healing and to minimize trade-offs (Figure 1). However, if this balance is not maintained and one of the two response overshoots, the chance to develop CKD as a consequence of endocycle-mediated hypertrophy and/or cancer as a consequence of hyperproliferation of renal progenitors becomes high (Figure 1). These novel insights have important clinical implications. First, we can now conclude that treating proteinuria, hypertension and hyperfiltration is not only important to avoid CKD progression, but also to promote podocyte regeneration and GFR improvement. Second, we must follow-up any patient with severe AKI for CKD [4] development and increased risk of (papillary) RCC.
Repair processes in the glomerulus and the tubule share similar mechanisms and costs. The glomerulus and the tubule both respond to injury using the same two strategies: hypertrophy of differentiated cells and regeneration of lost cells by renal progenitors. These two mechanisms happen at the same time after injury and have to be tightly balanced to optimize survival and tissue healing and avoid trade-offs. Indeed, overshooting of one response increases the risk for CKD, e.g. too many endocycling cells cannot maintain tissue function in the long run and too much progenitor cell proliferation increases the risk of kidney cancer.
CONFLICT OF INTEREST STATEMENT
The results presented in this article have not been published previously in whole or part, except in abstract format. The author has no conflicts of interest.
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