From kidney development to drug delivery and tissue engineering strategies in renal regenerative medicine

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Abstract

Deterioration of renal function is typically slow but progressive, and therefore renal disease is often diagnosed in a late stage when already serious complaints occur. Ultimately when renal function has dropped below 10%, renal replacement is required. Renal transplantation provides a long-term solution but due to shortage of donor kidneys most patients receive hemodialysis therapy. Although hemodialysis is an effect method to correct disturbances in water and electrolyte balances in the body, it does not substitute for the important endocrine and metabolic renal functions that are critical for homeostasis. Among these functions are, the renal production of renin which controls blood pressure, the secretion of erythropoietin which stimulates the synthesis of red blood cells, and the excretion of protein bound waste products. As a consequence, many dialysis patients remain in poor health. With the development of regenerative medicine, and particularly tissue engineering and novel drug delivery strategies, alternative routes for renal replacement are emerging. Increasing understanding of (stem) cells, growth factors and regeneration in the kidney has contributed to a whole new view on restoration and reconstruction of (parts of) renal tissue that may be used to improve current renal replacement therapies. Here, an overview of critical interactions between cells, growth factors and extracellular matrix molecules in kidney development and regeneration will be described. Ultimately, we will discuss how these interactions can be translated to strategies for in-vivo regeneration and in-vitro reconstruction of the kidney.

Graphical Abstract

Alternative routes for kidney replacement are emerging with the development of regenerative medicine, and particularly tissue engineering and novel drug delivery strategies. A combination of cells, factors and materials is used.

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Introduction

In the Western world end-stage renal disease (ESRD) is becoming an increasing clinical and economical burden [1]. Kidney patients need to undergo lifelong renal replacement therapy, which is very expensive and which puts a major burden on the quality of life. Renal transplantation is by far the best renal replacement therapy, but for many kidney patients this is not an option because of the shortage of donor organs, incompatibility problems, and the detrimental effects of long-term use of immunosuppressive drugs. The majority of patients depend on hemodialysis; a therapy that is based on the removal of small molecular waste products and the correction of electrolyte disturbances by passive diffusion over a semi-permeable membrane against a defined dialysis solution. Although the therapy effectively removes small waste molecules and to a lesser extent larger waste molecules, i.e. so-called ‘middle molecules’, medication is still required to control the calcium and phosphate levels and to compensate for the loss of renal production of erythropoietin (Epo) [2].

Until now, the clearance of uremic waste products, in particular the ‘middle molecules’ with a molecular weight of 500–6000 Da, and the protein-bound uremic toxins, by conventional dialysis therapy is highly inefficient [2]. Increasing the pore size and the permeability of the dialysis membranes improves the clearance of ‘middle molecules’ to a certain extent. Another major drawback of hemodialysis is the intermittent nature of the treatment. Nowadays, conventional hemodialysis treatment is performed for approximately 4 h thrice a week in specially equipped dialysis clinics. Hence hemodialysis is associated with large swings of the internal milieu that significantly contribute to cardiovascular complications [3]. This problem can be partially overcome by peritoneal dialysis. In this therapy the peritoneal membrane is used as a natural semi-permeable filter between the blood and the dialysis solution which is infused in the peritoneal cavity. This technique allows a better and more gradual removal of water and electrolytes, and gives the body more time to adjust. However, the net clearance rate that can be reached with this technique is lower than with hemodialysis. In the long run, fibrosis of the peritoneal membrane is inevitable, and many peritoneal dialysis patients switch to hemodialysis after a few years. In addition, peritoneal dialysis patients are highly susceptible to peritoneal infections.

With respect to dialysis efficiency the limits of the current techniques have almost been reached. Meanwhile, the number of kidney patients increases steadily. It is estimated that at least 8% of the population in the Western world have some evidence of mild renal disease, and are at risk to develop CRF. The rising costs associated with renal replacement therapy and the growing number of the kidney patients urge the quest for alternative therapies.

With the development of the interdisciplinary field of regenerative medicine [4], [5], [6], [7], the possibility of restoration of kidney tissue [8], [9], [10], [11], [12] using (stem) cells, regenerative factors, biomaterials, or combinations of these three, is approaching (Fig. 1). Therapeutic regenerative strategies can be aimed at either enhancing the body's regenerative capacity or at the reconstruction of new tissues, i.e. tissue engineering. Although regeneration of complete nephron structures in the kidney can only occur in the embryo, repair of damaged renal cells remains possible in adult life provided that the patient is still young and the damage is not too extensive. If that is the case, local delivery of growth factors and/or (stem) cells to enhance tissue reconstruction may be potentially effective. However, in chronically affected kidneys the damage is irreversible and the loss of tissue architecture makes regeneration virtually impossible.

For this large group of patients, the construction of tissue-engineered kidneys can be considered. This technique aims to reconstruct renal function by using renal epithelial cells that are grown on biomaterial scaffolds that guide proliferation, differentiation and maturation of renal tissue. However this technique is still in its infancy, and faces many hurdles that have not yet been overcome, such as the acquisition of large numbers of cells and the maintenance of viability and function ex vivo. Key to success is the reconstruction of the ‘regenerative niche’, i.e. the molecular interactions between growth factors, extracellular matrix materials and cells. However, questions arise such as: How does the regenerative niche look like? Which factors are important and which are redundant? It is now that answers to these questions are beginning to emerge. In many ways, renal regeneration is reminiscent of renal development [13], [14], [15], [16].

This article will give an overview of the field of renal regenerative medicine with respect to engineering concepts using cells, materials and/or regenerative factors. However, basic knowledge about the kidney is essential, which we firstly describe. Furthermore, to unravel the ‘renal regenerative niche’, molecular interactions involved in nephrogenesis and renal regeneration have to be taken into account. Finally, the account will end with our approach to renal regenerative medicine.

Section snippets

Kidney anatomy and function

Our kidneys play an essential role in maintaining body homeostasis by excreting excess water, regulating the chemical composition of the blood, removing waste products, and producing important hormones that help to maintain blood pressure, keep healthy bones and prevent anemia [2]. Specific hormones that are produced by the kidneys are renin, erythropoietin, vitamin D and prostaglandins. The kidney can be roughly divided into three parts: the outer part which is the cortex, the middle section

Mesenchymal-to-epithelial transition

The kidneys are formed by a complex interplay between two embryonic structures: the ureteric bud and the metanephric mesenchyme [2]. The ureteric bud is an outgrowth of the mesonephric duct and gives rise to the collecting duct system. The ureteric bud induces the metanephric mesenchyme around its tips to form the Bowman's capsule, the proximal tubule, the loop of Henle and the distal tubule. This nephron formation requires epithelialization, which occurs by reciprocal signaling between the

The quest for resident renal stem/progenitor cells

During kidney regeneration, the renal embryonic program is partially recapitulated. However, no complete nephron structures can be formed in the regeneration process. Nevertheless, during adult life the renal tissue is maintained by slow turnover of cells. Only in response to injury, the number of proliferating cells in the kidney, in particular in the proximal tubular part of the nephron, rapidly increases. The increase in proliferation is associated with the re-expression of developmental

Novel therapies

Alternative therapies are proposed to be developed via two strategies: i. development of early detection methods and smart renal regeneration therapies, in order to intervene in and cure kidney diseases at an early stage, and ii. design and development of alternative renal replacement therapies, such as a bioartificial kidney (devices) using tissue engineering strategies. As discussed, the possibility of restoration of kidney tissue [8], [9], [10], [11] using cells, regenerative factors,

General conclusion

Alternative therapies for hemodialysis and renal transplantation using different approaches based on renal regeneration using (stem) cells or regenerative factors, or renal bioengineering applying biomaterials, were discussed. Owing to its complex structure, its composition with approximately 1 million nephrons consisting of more than 15 cell types with different functions, it is difficult to specifically influence and/or engineer a part of the kidney. Using regenerative medicine the complex

Acknowledgements

We thank Marco Harmsen, Guido Krenning and Tonny Bosman for useful discussions. This work is supported by SupraPolix, the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO), and the Dutch Kidney Foundation.

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