Ariela Benigni

Pharmacological Induction of Kidney Regeneration

The incidence of kidney disease is increasing worldwide, becoming one of the major public health problems. Until recently, the kidney was considered an organ with a limited capacity for repair and the progression to end-stage renal disease has generally been considered inexorable. Technological advances in the field of three-dimensional visualization of organ ultrastructure made in recent decades, together with the identification of renal progenitor cells lining the Bowman’s capsule of adult rat and human kidneys, have allowed to prove that tissue repair in the adult kidney is possible, even in mammals. Experimental and clinical studies that aim to identify drugs capable to influence renal progenitors fate and/or interfere with the pathogenetic pathways underlying renal disease progression have great potential for future kidney regeneration.

The Onset and Resolution of Renal Fibrosis: A Human Perspective

Abstract Renal fibrosis is a common hallmark of chronic kidney disease (CKD) and a major determinant of progressive renal function loss. Angiotensin II (Ang II), transforming growth factor-β1 (TGF-β1), and their downstream effector, connective tissue growth factor (CTGF), have a key role in the onset and progression of renal fibrosis. Recent advances in the field have disclosed endogenous counter-regulators of Ang II and TGF-β1 signaling intrinsic to the renin–angiotensin system (RAS) and TGF-β superfamily that may hold therapeutic potential for fibrotic kidney disease. An RAS blockade-based multimodal approach is the current treatment in CKD patients, and drugs targeting TGF-β and CTGF have entered phase I and II clinical trials. Epigenetic control of renal fibrogenesis affects individual heterogeneity of progression rates of CKD. Smad3-dependent miRNAs may offer fine-tuning regulation in TGF-β–mediated fibrosis and may represent novel targets for future therapeutic approach. Epigenetic therapeutics is still at a preclinical experimentation stage.

Therapeutic Options for Preventing Transplant-Related Progressive Renal and Vascular Injury

The first organ transplantation occurred in 1954 in Boston under the direction of Joseph Murray: a kidney removed from a healthy donor and transplanted into his identical twin promptly started to function, and the recipient survived for 9 years. Since then, attempts to suppress the recipient’s immune system were pursued with the aim to extend the possibility of transplantation beyond involving identical twins.1 The first approach to suppress the rejection process employing the use of sublethal total-body irradiation combined with cortisone had a poor outcome, however. The rate of successful transplantation of kidneys from cadaveric donors and familial human leukocyte antigen (HLA)-matched living donors slowly increased during the 1960s and early 1970s following the introduction of azathioprine with corticosteroids.1 But a prolonged use of corticosteroids was the cause of high mortality due to excessive immunosuppression. Only the introduction of cyclosporine in 1980 really improved the rate of 1-year graft survival from 70 to more than 80%.2

Molecular Medicine in Organ Transplantation: How and When?

Short-term graft survival has been remarkably improved in the past two decades thanks to increased skill coupled with new immunosuppressants. Although 1 year graft survival is now close to 85–90%, at least for cadaver kidney transplant, long-term results are less impresssive [1] despite recent data open new hopes. Data from the UNOS registry in more than 93,000 patients who had a renal transplant between the years 1988–1996 showed a projected graft half-life of 21.6 years living and 13.8 years for cadaver donors, respectively [S. Hariharan, personal communication]. The remark-able success is mostly related to the ability of new anti-rejection drugs to limit acute rejections within the first year post surgery. Whether these important findings can be extended also to other transplants is unknown at the present, so that up to now the half-life for most organs other than kidney is only 9.9 years, with no substantial improvement over the past 20 years. Medications moreover have to be given long-life, which invariably impairs systemic immunity translating in more risk of infections and cancers. Tumors of viral origin, including non-Hodgkin’s lymphoma, squamous cell-carcinoma of the skin, and Kaposi’s sarcoma are 6.5 times more common in transplant recipients than in the general population [2], and their frequency is estimated to increase with time.