Opinion

Minimal change disease and idiopathic focal segmental glomerulosclerosis are often described as separate disease entities. Here, the authors propose that they are in fact different manifestations of the same disease process and review the evidence that led to this hypothesis.

Atypical haemolytic uraemic syndrome (aHUS) is associated with genetic or autoimmune defects that affect the complement system; however, the identification of mutations in diacylglycerol kinase ε (DGKE) as the cause of a recessive form of aHUS characterized by proteinuria highlighted podocyte dysfunction as a potential complication of aHUS. Here, Marina Noris et al. discuss the mechanisms by which DGKE deficiency might lead to aHUS and podocyte dysfunction, and the possible links between DGKEand the complement system.

A prematurely aged phenotype is a common characteristic of chronic kidney disease (CKD) and other chronic organ diseases, including heart failure and rheumatoid arthritis. In this opinion article, the authors suggest four major pathophysiological mechanisms that may underlie premature ageing in CKD.

Drug trial and approval processes are often affected by the conflicting interests of regulatory authorities, academia, and the pharmaceutical industry. In this Perspectives article, Silvio Garattini and Norberto Perico discuss examples of particular relevance to therapeutic interventions in nephrology, to highlight and summarize flaws in the current drug development process. The authors call on academia to develop more-effective relationships with both regulatory authorities and the pharmaceutical industry to balance public needs with commercial aims.

Recurrent dehydration and salt loss might be a mechanism that causes chronic kidney disease, whereby increased plasma osmolarity activates both intrarenal (polyol-fructokinase) and extrarenal (vasopressin) pathways to drive injury. The authors propose that water and salt influence blood pressure through the timing and combination of their intake, affecting plasma osmolarity and intrarenal and extrarenal mechanisms of renal injury.

Haemolytic uraemic syndrome (HUS) leads to anaemia, thrombocytopenia and, ultimately, acute renal failure. Some patients are also at risk of cardiovascular complications owing to mutations in the complement pathway, which result in microangiopathic injury of the coronary vasculature. This Perspectives article highlights the cardiovascular complications arising in patients with HUS and the implications for treatment of this rare disease.

The underlying cause of hypertension is unknown in the vast majority of patients with high blood pressure. This Perspectives article discusses the role of T cells in renal inflammation and how autoimmunity, mediated by heat shock proteins, leads to salt-sensitive hypertension.

As the prevalence of chronic kidney disease increases, new strategies to reverse or prevent tissue damage are under investigation. Here, Rabelink and Little describe progenitor cell populations that may have a key role in tissue repair and regeneration in the kidney. They also discuss the potential to harness the innate regenerative capacity of the kidney in the context of ongoing studies of mesenchymal stromal cell therapy.

Acute kidney injury (AKI) is a growing problem in hospitalized patients and is associated with adverse outcomes. Recognizing renal injury earlier—at the stage of 'incipient AKI'—may enable renoprotective strategies to be initiated at a time when more kidney tissue is salvageable. In this article, the authors propose three strategies that may preserve kidney function and minimize further kidney injury in patients with 'incipient AKI'.

A strong inter-relationship seems to exist between the peritoneal membrane and the kidney in patients on peritoneal dialysis. In this Perspectives article, Nessim and Bargman describe examples of this interplay—such as the mechanisms by which alterations in peritoneal membrane function may influence residual renal function and vice versa—and propose that this interplay be characterized by a new term: 'peritoneal–renal syndrome'.

Variants in two neighbouring genes,APOL1 and MYH9, have previously been associated with kidney disease. Here, using 1000 genomes data, the authors reason by exclusion that the APOL1variants are in fact the most likely causal variants involved in kidney disease, and that this genomic region should be targeted in future studies to determine function.

Advances in molecular genetics and genomic science are improving our understanding of the molecular basis of nephrotic syndrome. However, the availability of genetic testing in the management of nephrotic syndrome poses unique challenges for clinicians in terms of who to test and how best to use the information obtained. Here, the authors present their collective opinion on the clinical indications for and the utility of genetic testing in monogenic nephrotic syndrome based on the evidence available to date.

Prospective cohort studies have shown that anaemia is an independent predictor of adverse outcomes in patients with chronic kidney disease. However, randomized controlled trials of the use of erythropoiesis-stimulating agents to correct moderate anaemia in this patient group have failed to show clinical benefit, and indicate that such treatment may even be harmful. Here, Patrick Parfrey discusses possible explanations for these seemingly contradictory results.

Emerging evidence suggests that 15–20% of patients who do not fulfill current consensus criteria for AKI have acute tubular damage, which is associated with adverse outcomes. Haase et al. argue that the spectrum of AKI should be extended to incorporate subclinical forms of the disorder diagnosed on the basis of biomarkers of tubular damage.

Fibroblast growth factor 23 (FGF23) is a hormone involved in bone and mineral metabolism. Increased FGF23 levels are associated with poor clinical outcomes in patients with kidney disease and could represent a novel biomarker and therapeutic target. In this article, Komaba and Fukagawa provide an overview of the physiological role of FGF23 and discuss the Klotho-dependent and Klotho-independent effects of FGF23 in disease.

Klotho deficiency is now considered an early event in acute kidney injury (AKI), and a pathogenic factor that contributes to kidney damage. Here, the authors discuss why this renal-derived protein is a highly promising candidate as both an early biomarker and therapeutic agent for AKI.

The Declaration of Istanbul on Organ Trafficking and Transplant Tourism was formulated at an international meeting held in 2008 with the aim of promoting the welfare of living organ donors in the context of improved global organ transplantation practice. In this Perspectives article, Danovitch and Al-Mousawi provide an update on this endeavor, specifically discussing promulgation of the Declaration, how it has been put into action and legislative changes that have since come into effect.

The slowly progressing nature of chronic kidney disease makes the design of clinical trials with hard end points extremely challenging. One way of establishing a drug's effectiveness is by demonstrating an effect on a surrogate end point. In this Perspectives article, the authors describe data supporting proteinuria as a valuable predictor of renal survival and argue that it should be used as a surrogate marker of renal disease progression in renal clinical trials.

In this Perspectives article, Aliza Thompson from the FDA's Division of Cardiovascular and Renal Products argues that existing data do not support the adoption of proteinuria as a general-purpose surrogate end point for establishing a drug's effectiveness in treating chronic kidney disease. She suggests, however, that it may be reasonable to use changes in proteinuria as a basis for the accelerated approval of a drug if certain conditions are met.

Revascularization alone might be sufficient to restore kidney function and regenerate the structure of the diseased kidney. In this Perspectives article, David Long, Jill Norman and Leon Fine provide an overview of how revascularization might be achieved using vascular growth factors or adoptive transfer of endothelial progenitor cells. The authors also describe how therapeutic strategies targeting the microvasculature could be enhanced in the future.