Regenerative Medicine Kidney Disease

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Spotlight On Genetic Kidney Diseases: A Call For Drug Delivery And Nanomedicine Solutions

By Cinzia Rota Cinzia Rota Scilit Preprints.org Google Scholar , Marina Morigi Marina Morigi Scilit Preprints.org Google Scholar * and Barbara Imberti Barbara Imberti Scilit Preprints.org Google Scholar

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy

The prevalence of renal diseases is emerging as a public health problem. Despite major progress in supportive therapy, mortality rates among patients remain high. In an attempt to find innovative treatments to stimulate kidney regeneration, stem cell-based technology has been proposed as a potentially promising strategy. Here, we summarise the renoprotective potential of pluripotent and adult stem cell therapy in experimental models of acute and chronic kidney injury and we explore the different mechanisms at the basis of stem cell-induced kidney regeneration. Specifically, cell engraftment, incorporation into renal structures, or paracrine activities of embryonic or induced pluripotent stem cells as well as mesenchymal stem cells and renal precursors are analysed. We also discuss the relevance of stem cell secretome-derived bioproducts, including soluble factors and extracellular vesicles, and the option of using them as cell-free therapy to induce reparative processes. The translation of the experimental results into clinical trials is also addressed, highlighting the safety and feasibility of stem cell treatments in patients with kidney injury.

Cardiovascular Events With Finerenone In Kidney Disease And Type 2 Diabetes

The increasing incidence of kidney diseases raises considerable concerns regarding human health worldwide. The pressure to find new strategies to prevent or halt the progression, or resolve kidney disease, is driven by the limited availability of therapies.

The long path towards understanding how the kidney works and how it can be protected and healed began over two centuries ago [1].

Since then, great progress has been made, beginning with basic science in the mid-1800s, which furthered our knowledge of renal filtration and fluid maintenance, up until the breakthrough in the 1940s of the first attempt to create an artificial kidney [2]. The decades that followed were characterised by the first long-term successful human kidney transplantation from a living donor carried out by Dr Joseph Murray, who received the Nobel Prize in Medicine for this achievement [3, 4]. This was a huge step forward but highlighted the need to better understand the immune system to prevent rejection [5]. Further significant improvements were pursued later in the 1980s, which were achieved by the introduction of HLA-DR matching and the use of immunosuppressive agents, such as cyclosporine.

Stem Cell Therapy For Kidney Failure: Comprehensive Overview (2023)

The introduction in the 1960s of outpatient dialysis, a development that has had a great impact on patient quality of life, brought new hope to patients with chronic kidney diseases [6, 7]. Since then, the new goal of delaying the progression of kidney disease was achieved through the discovery of drugs that inhibit the renin angiotensin aldosterone system (RAAS) [8]. It is not currently clear what the next necessary step is, but it seems to be in the direction of regenerative medicine. A number of studies in recent years have attempted to identify the underlying mechanisms of renal repair in order to explore the potential regenerative capacity of the kidneys. The main objective of this research has been to ascertain whether the regenerative capacity of adult kidneys can be supported by terminally differentiated cells, whether there are multipotent progenitor cells in the kidney and whether therapy with stem cells of extrarenal origin can contribute to renal repair, favouring or accelerating the regenerative process. Many papers have reported on the potential use of stem cells of different origins for treating many different pathologies, including kidney diseases. The efficacy, to varying extents, of using stem cells from different sources in models of acute kidney injury (AKI) and chronic kidney diseases (CKD) has been demonstrated experimentally. The field has generated great expectations, from the initial, widely dismissed results of stem cell integration into host renal tissue, to the paracrine hypothesis of stem cell-mediated repair. However, clinical translation of the experimental findings does not seem to be a realistic prospect in the near future, due principally to the lack of robustness of experimental data and to clinical studies that have been limited by modest outcomes and the small number of patients enrolled (Table 1, Figure 1). Before moving on to clinical applicability, many issues must still be resolved, including identifying the best cell types, the route and timing of administration, and the dose of cells necessary for different pathological conditions.

This review describes a wide range of pre-clinical reports on stem cell-based therapy in experimental AKI and CKD, summarizing current knowledge and discussing criticisms for moving to the clinic.

Kidney disease is a severe health problem that affects over 10% of the global population and accounts for 5 to 10 million deaths annually mainly due to the progressive increase in obesity, diabetes, hypertension and cardiovascular disease [27]. Kidney diseases have been traditionally classified into two separated pathologies, acute kidney injury (AKI) and chronic kidney disease (CKD), even though a strict interconnection with regard to their aetiology has been recently highlighted [28]. AKI is a common clinical problem in critically ill patients with an incidence that varies between 15% and 50% [29] and it is associated with short- and long-term morbidity and mortality. AKI is characterised by the abrupt impairment of renal function, which can have pre-renal (i.e., hypoperfusion), intra-renal (i.e., nephrotoxic agents) or post-renal (obstruction of urinary tract) causes [30]. AKI is characterised by damage to the proximal tubular cells, which, unable to maintain adequate energy production, undergo apoptosis, detach and obstruct the lumen leading to increased intratubular pressure and “backleak” of filtrate contributing to dysfunction. In parallel, endothelial cell injury results in vascular rarefaction. AKI manifests clinically when a sudden increase in serum creatinine and nitrogen metabolites, reflecting a reduction in the glomerular filtration rate (GFR), or an abrupt reduction in urine output occurs [31]. As too many cases of AKI are diagnosed too late, major efforts are being made to discover biomarkers that can be used as early predictors of AKI. Some of these include mediators of inflammation (neutrophil gelatinase–associated lipocalin, IL-8), markers of changes in renal structure (kidney injury molecule-1), enzymes (alkaline phosphates, and alanine aminopeptidase) [32]. The management of AKI depends on its aetiology because the primary reversible cause of injury should be removed wherever possible. Nephrotoxic drugs should be avoided and fluid resuscitation and diuretic administration should be used to treat volume overload, even when they do not facilitate AKI recovery or reduce mortality [33]. Renal replacement therapy can also be required as a life-sustaining support strategy. Major efforts are being made to identify new targets for managing AKI, including molecules that act on hemodynamics, inflammation and oxidative states, cellular metabolism and mitochondrial function [34].

What Has Been Achieved In Tissue Engineering And Regenerative Medicine?

Clinical and experimental investigations have found an interconnected link between AKI and the development of CKD [35, 36, 37, 38, 39, 40]. CKD can also be triggered by different risk factors, including cardiovascular pathologies, diabetes, nephrectomy, toxic insults, etc. The prevalence of CKD is rising worldwide, affecting about 18% of the global population [27]. CKD is a syndrome characterised by persistent changes to the kidney structure and function, which decreases progressively and is associated with nephron loss, glomerular hypertrophy, podocyte detachment and the formation of sclerotic lesions. Moreover, the atrophy of nephrons is accompanied by immune cell infiltration and interstitial fibrosis [41].

There are few therapeutic options for restoring a kidney affected by chronic disease [27] and the disease is often diagnosed too late because the initial stages can be asymptomatic. Severely damaged kidneys may progress to kidney fibrosis and end-stage renal disease (ESRD). ESRD requires renal replacement therapy that aims to substitute critical kidney function and consists of dialysis or kidney transplantation. As hypertension is recognised as one of the causes of CKD, the therapy for CKD patients is currently based on the use of drugs for blood pressure control and for inhibition of the renin-angiotensin aldosterone system, which plays a central role in controlling blood pressure. Only when treatment is started early, can the progression to ESRD be retarded. Therefore, new

The introduction in the 1960s of outpatient dialysis, a development that has had a great impact on patient quality of life, brought new hope to patients with chronic kidney diseases [6, 7]. Since then, the new goal of delaying the progression of kidney disease was achieved through the discovery of drugs that inhibit the renin angiotensin aldosterone system (RAAS) [8]. It is not currently clear what the next necessary step is, but it seems to be in the direction of regenerative medicine. A number of studies in recent years have attempted to identify the underlying mechanisms of renal repair in order to explore the potential regenerative capacity of the kidneys. The main objective of this research has been to ascertain whether the regenerative capacity of adult kidneys can be supported by terminally differentiated cells, whether there are multipotent progenitor cells in the kidney and whether therapy with stem cells of extrarenal origin can contribute to renal repair, favouring or accelerating the regenerative process. Many papers have reported on the potential use of stem cells of different origins for treating many different pathologies, including kidney diseases. The efficacy, to varying extents, of using stem cells from different sources in models of acute kidney injury (AKI) and chronic kidney diseases (CKD) has been demonstrated experimentally. The field has generated great expectations, from the initial, widely dismissed results of stem cell integration into host renal tissue, to the paracrine hypothesis of stem cell-mediated repair. However, clinical translation of the experimental findings does not seem to be a realistic prospect in the near future, due principally to the lack of robustness of experimental data and to clinical studies that have been limited by modest outcomes and the small number of patients enrolled (Table 1, Figure 1). Before moving on to clinical applicability, many issues must still be resolved, including identifying the best cell types, the route and timing of administration, and the dose of cells necessary for different pathological conditions.

This review describes a wide range of pre-clinical reports on stem cell-based therapy in experimental AKI and CKD, summarizing current knowledge and discussing criticisms for moving to the clinic.

Kidney disease is a severe health problem that affects over 10% of the global population and accounts for 5 to 10 million deaths annually mainly due to the progressive increase in obesity, diabetes, hypertension and cardiovascular disease [27]. Kidney diseases have been traditionally classified into two separated pathologies, acute kidney injury (AKI) and chronic kidney disease (CKD), even though a strict interconnection with regard to their aetiology has been recently highlighted [28]. AKI is a common clinical problem in critically ill patients with an incidence that varies between 15% and 50% [29] and it is associated with short- and long-term morbidity and mortality. AKI is characterised by the abrupt impairment of renal function, which can have pre-renal (i.e., hypoperfusion), intra-renal (i.e., nephrotoxic agents) or post-renal (obstruction of urinary tract) causes [30]. AKI is characterised by damage to the proximal tubular cells, which, unable to maintain adequate energy production, undergo apoptosis, detach and obstruct the lumen leading to increased intratubular pressure and “backleak” of filtrate contributing to dysfunction. In parallel, endothelial cell injury results in vascular rarefaction. AKI manifests clinically when a sudden increase in serum creatinine and nitrogen metabolites, reflecting a reduction in the glomerular filtration rate (GFR), or an abrupt reduction in urine output occurs [31]. As too many cases of AKI are diagnosed too late, major efforts are being made to discover biomarkers that can be used as early predictors of AKI. Some of these include mediators of inflammation (neutrophil gelatinase–associated lipocalin, IL-8), markers of changes in renal structure (kidney injury molecule-1), enzymes (alkaline phosphates, and alanine aminopeptidase) [32]. The management of AKI depends on its aetiology because the primary reversible cause of injury should be removed wherever possible. Nephrotoxic drugs should be avoided and fluid resuscitation and diuretic administration should be used to treat volume overload, even when they do not facilitate AKI recovery or reduce mortality [33]. Renal replacement therapy can also be required as a life-sustaining support strategy. Major efforts are being made to identify new targets for managing AKI, including molecules that act on hemodynamics, inflammation and oxidative states, cellular metabolism and mitochondrial function [34].

What Has Been Achieved In Tissue Engineering And Regenerative Medicine?

Clinical and experimental investigations have found an interconnected link between AKI and the development of CKD [35, 36, 37, 38, 39, 40]. CKD can also be triggered by different risk factors, including cardiovascular pathologies, diabetes, nephrectomy, toxic insults, etc. The prevalence of CKD is rising worldwide, affecting about 18% of the global population [27]. CKD is a syndrome characterised by persistent changes to the kidney structure and function, which decreases progressively and is associated with nephron loss, glomerular hypertrophy, podocyte detachment and the formation of sclerotic lesions. Moreover, the atrophy of nephrons is accompanied by immune cell infiltration and interstitial fibrosis [41].

There are few therapeutic options for restoring a kidney affected by chronic disease [27] and the disease is often diagnosed too late because the initial stages can be asymptomatic. Severely damaged kidneys may progress to kidney fibrosis and end-stage renal disease (ESRD). ESRD requires renal replacement therapy that aims to substitute critical kidney function and consists of dialysis or kidney transplantation. As hypertension is recognised as one of the causes of CKD, the therapy for CKD patients is currently based on the use of drugs for blood pressure control and for inhibition of the renin-angiotensin aldosterone system, which plays a central role in controlling blood pressure. Only when treatment is started early, can the progression to ESRD be retarded. Therefore, new