Regenerative medicine of the kidney

Abstract

End stage renal disease is a major health problem in this country and worldwide. Although dialysis and kidney transplantation are currently used to treat this condition, kidney regeneration resulting in complete healing would be a desirable alternative. In this review we focus our attention on current therapeutic approaches used clinically to delay the onset of kidney failure. In addition we describe novel approaches, like Tissue Engineering, Stem cell Applications, Gene Therapy, and Renal Replacement Therapy that may one day be possible alternative therapies for patients with the hope of delaying kidney failure or even stopping the progression of renal disease.

Introduction

Every year the number of patients diagnosed with ESRD (End Stage Renal Disease) increases exponentially creating urgency for clinicians and scientists to search out new approaches that will someday improve the treatment of patients with renal disease [1]. Acute kidney failure (AKF) is represented by a rapid decrease in renal function usually accompanied by an increase in creatinine and other physiologic parameters over several days. Some of the major causes of AKF include the following: inadequate renal perfusion, hemorrhage and loss of intravascular fluid, low cardiac output, low systemic vascular resistance, acute tubular injury, glomerulonephritis, as well as, urinary obstruction. Chronic kidney disease (CKD), on the other hand, is characterized by a long-standing, progressive deterioration of renal function. These symptoms develop slowly leading to ESRD. The most common cause of CKD in the US is diabetic nephropathy, followed by hypertensive nephroangiosclerosis and various glomerulopathies, such as IgA nephropathy. In comparison, some of the hereditary nephropathies, such as Policystic Kidney Disease or Alport Syndrome, can also lead to more than 75% loss of the renal function reducing drastically the glomerular filtration rate.

The principal “renoprotective strategies” to delay ESRD focus on the efficient control of blood pressure and minimization of proteinuria with administration of important pharmacological agents in combination with antagonists of the Renal Angiotensin System (RAS), for example, ACEIs [2]. However, renoprotection is not an efficient long term solution. In fact, the majority of ESRD patients are on Renal Replacement Therapy (RRT), specifically on diffusion-based hemodialysis (HD) and only a small percent of these patients can receive organ transplantation due to limited number of organ donors [3]. Even if dialysis is the only available treatment, in combination with an organ transplant, morbidity and mortality in these patients still remain significantly high. This is in part due to the unphysiological filtration properties of HD, the suboptimal quality of life for large number of these patients, and the very high treatment costs. Renal transplantation is considered the best option for prolonging life in most ESRD patients, and is longitudinally more cost effective compared to other treatment measures. However, shortage in donor numbers and complications with immunosuppressive drugs underscore the need for possibly better alternative therapies for ESRD patients.

One of the major challenges in Regenerative Medicine, in particular the field of kidney regeneration, is improvement of current therapies coupled with discoveries of new approaches to treat patients suffering from acute and chronic kidney disease. An ideal form of RRT would create a devise that would imitate precisely the kidney's physiological activity, removing solutes and water based on patient needs. It needs to be biocompatible, implantable, low cost, reliable and of course safe. On the other hand, organ transplantation therapy would surely benefit from an increasing availability of donor organs, as well as through improvement of immunosuppressive regimens with less toxicity. Finally, xenotransplantation from different species could also be a viable alternative one-day. Therefore, while a number of researchers are working on improving current therapies, other groups are directing their efforts towards new alternative ways to treat kidney failure (Fig. 1). In particular, Tissue Engineering and Stem Cell Therapies are the major new fields of investigation in renal regeneration. The idea of recreating a de novo ex vivo kidney using scaffolds as a skeleton in which to seed renal cells or stem cells would be an ideal solution for organ shortages. Alternatively, the application of stem cells, endogenous as well as exogenous, may be a feasible approach to slowing the progression of chronic kidney disease. In this review, we will summarize some of the major efforts applied to improving the already available treatments for ESRD using technologies of RRT. We intend to discuss some of the basic science approaches, ranging from stem cells, to cloning and Tissue Engineering; including results obtained until now and future directions.