Introduction: Hearing footsteps of the future

Chronic kidney disease (CKD) is a major global public health problem. In developed countries, diabetic nephropathy and hypertensive nephrosclerosis are major causes of CKD, with glomerulonephritis also accounting for a significant number of patients with CKD. Adverse outcomes of CKD include cardiovascular events in addition to end-stage kidney disease requiring renal replacement therapies. Although strict control of blood pressure via blockade of the renin– angiotensin system effectively retards the progression of CKD, there is considerable interindividual variation in terms of the response. Furthermore, although such treatment can delay the progression of disease, it cannot halt the clinical course completely. In order to improve the prognosis and quality of life of patients with CKD and reduce medical costs, it is essential to understand the pathophysiological mechanisms driving the initiation and progression of CKD in order to enable the development of novel therapeutic approaches. This special series of articles comprises five invited reviews from some of the world’s leading nephrology groups and describe recent breakthroughs in this field. Kidneys with advanced CKD are always fibrotic and fibrosis of the kidney is the common end-point of virtually all progressive kidney disease. Thus, the mechanisms mediating fibrotic changes in the kidney have been a focus of intensive research. The pathogenesis of renal fibrosis is characterized by progressive and excessive accumulation of extracellular matrix components and replacement of epithelial and endothelial cells with fibroblasts. The fundamental questions in this field include: what are the soluble factors that stimulate fibrotic changes; what are the cell-types that produce such large amounts of extracellular matrix proteins; what cell-types serve as the precursors for fibroblasts; and how are these processes regulated? Transforming growth factor (TGF)-b and connective tissue growth factors are essential in glomerular sclerosis and fibrosis of the tubulointerstitium. The platelet-derived growth factor (PDGF) system, comprising four isoforms (PDGF-A, -B, -C and -D) and two receptor chains (PDGFR-a and -b), regulates a multitude of pathophysiological events, ranging from cell proliferation and migration to extracellular matrix accumulation, the production of proand anti-inflammatory mediators, tissue permeability and regulation of haemodynamics. Fibroblast growth factor 23 plays a crucial role in the pathogenesis of mineral and bone disorders in CKD. Vascular endothelial growth factor is another important soluble factor in kidney disease, but its role in fibrosis remains to be determined. In this series, Boor and Floege discuss the fibrotic roles of growth factors such as TGF-b and connective tissue growth factor, as well as an antifibrotic role for bone morphogenetic protein-7. They also discuss the roles of PDGF, for which potential clinical tools such as a neutralizing antibody and an inhibitor of the receptor kinase are available. Their review highlights the potential roles of these factors as biomarkers in CKD. After reading this article, readers will have an up-to-date understanding of the roles of these essential cytokines in CKD, as well as the limitations of the available experimental data. There has recently been intense debate regarding the source of fibroblasts in the kidney in CKD. Recent studies by Humphreys et al. have shed new light on this field. Kidney pericytes envelop adjacent capillary endothelial cells. The article by Kida and Duffield clearly describes pericyte activation and differentiation into scarforming myofibroblasts, serving as the major source of myofibroblasts in the fibrotic kidney. Furthermore, pericyte detachment in response to kidney injury leaves an unstable microvasculature, which leads to capillary rarefaction and fibrosis. Capillary rarefaction and fibrosis are intricately linked with hypoxia of the kidney, a crucial mediator of progression of CKD, as described below. The article by Kida and Duffield opens a new avenue in kidney fibrosis research and will convince readers that investigations into the cross-talk between kidney pericytes and endothelial pericytes will identify novel therapeutic targets for CKD. Progression of CKD is irreversible once renal damage reaches a certain threshold. Although glomerular hypertension is the final common pathway to glomerulosclerosis, close pathological analysis shows that functional impairment of the kidney is better correlated with the degree of tubulointerstitial damage than with the degree of glomerular injury. Accumulating evidence suggests that hypoxia in the tubulointerstitium also plays a crucial role as the final common pathway to end-stage kidney disease. Detailed mechanisms linking fibrogenesis and hypoxia are discussed by Palm and Nordquist in this series. Oxygenation of the organ is determined by the supply and demand of oxygen by resident cells. The kidney suffers from inefficient uptake of oxygen due, in part, to arterial-to-venous oxygen shunting. Although various means of detecting hypoxia, such as pimonidazole, are used in experimental studies, polarographic oxygen sensors can measure regional oxygen tensions directly and remain as the (currently) most accurate technique to gain further insight into the important area of kidney hypoxia. Palm and Clinical and Experimental Pharmacology and Physiology (2011) 38, 438–440