The final paper of The Lancet Series on Renal Medicine addresses the research into kidney regeneration, and how and if it could be possible in humans, as it is in fish. The paper is by Giuseppe Remuzzi, Ariela Benigni, and Marina Morigi, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Members of both the plant and animal kingdoms survive damage because of regeneration strategies, such as preservation of stem-cell niches in adult life or induction of stem-cell potential in differentiated cells—this is cells that have already developed into their final form and function. The axolotl—a Salamander found in Mexico—is capable of limb regeneration after losing a limb. During limb regeneration, adult tissue of the salamander near the plane of amputation is converted into a zone of undifferentiated progenitor* cells, called the blastema, that reforms the different tissues of the limb.
For the kidney, which has a restricted intrinsic ability to regenerate, the search for specific renal progenitor* or stem cells is ongoing. A number of studies have indicated that both of these cells could exist. For stem cells, investigations have focused on identification of cells expressing stem cell markers, and also on finding cells in the kidney that share functional properties of stem cells.
Adult stem cells derived from bone marrow might contribute to turnover and regeneration of several compartments of the kidney. Bone-marrow cells are known to migrate to the kidney and participate in normal tubular epithelial cell turnover and repair after acute kidney injury.
The authors say: "Improved understanding of the mechanisms of kidney repair has stimulated researchers to clarify whether supplementary cells injected into an acutely damaged kidney might aid repair and regeneration of injured tissue, thus accelerating and augmenting the ongoing natural healing process. Adult stem cells, either derived from bone marrow or of renal origin might participate in cellular repair and tissue remodelling after acute renal injury."
However, the authors also question whether or not chronic kidney damage—with many different causes—can also be repaired. They discuss the importance of drug treatment using angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type I receptor blockers (ARBs) in prevention and regression of renal damage, by reducing hypertension within and protein excretion by the kidneys. Wilmer and coworkers reported that 8-year ACE inhibitor therapy stabilised kidney function in six patients with type 1 diabetes, and that nephrotic syndrome otherwise predicted progression to end-stage kidney disease in months. Evidence from this and other studies suggest that ACE inhibitors might be permissive for kidney repair and regeneration—ie, as well as exerting direct effects they may allow stem cells to repair the underlying pathological damage within the kidney. Despite these positive findings, years of such drug therapy are needed before clinically appreciable benefits in kidney function can be recorded. The authors suggest one strategy could be ACE inhibitors at much higher doses than usually recommended for blood pressure control, in combination with an ARB and a diuretic. Such a strategy, when trialled on 112 patients, resulted in only 2 of 56 patients progressing to end-stage kidney disease, compared with 17 of 56 controls.
The authors conclude: "Studies in man will improve the understanding of the genetics governing progression and regression of chronic kidney disease and genes associated with favourable outcomes. Enhanced understanding of mechanisms of action of already available drugs with renoprotective capacity will pave the way to unravel novel pathways that are possibly relevant to renal repair. Together, insights from human genetics and mechanistic studies on renoprotection will contribute to the design of molecules targeted to genes relevant to the pathophysiology of regeneration, with the goal of kidney regeneration instead of dialysis or renal transplantation."
Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research, Bergamo, Italy. T) +39-035 319888 E) giuseppe.remuzzi@marionegri.it
Ariela Benigni, Mario Negri Institute for Pharmacological Research, Bergamo, Italy. T) +39-035-319888 E) ariela.benigni@marionegri.it
For full Series paper 3, see: http://press.thelancet.com/renal3.pdf
Note to editors: * Adult stem cells or progenitor cells-Present in adult tissues; have clonogenic, self-renewing ability and give rise to terminally differentiated cells of the tissue of origin and to other different lineages. For other definitions see panel page 1311 full paper.
Journal
The Lancet