Reviews & Analysis

New data from the BENEFIT study demonstrate that belatacept improves long-term allograft and patient survival after kidney transplantation, despite higher rates of biopsy-proven acute rejection than with ciclosporin. The noninferiority design of BENEFIT represents a feasible strategy to further the development of innovator drugs to reduce late graft loss.

Clinical trials in patients with acute kidney injury (AKI) have been stymied by a lack of consensus on suitable renal-specific end points. In a recent analysis, Grams et al. suggest that a sustained 30–40% reduction in estimated glomerular filtration rate after hospital discharge might be a suitable intermediate end point for AKI clinical trials.

Graft necrosis resulting from ischaemia–reperfusion injury leads to the release of endogenous molecules — damage-associated molecular patterns (DAMPs) — which trigger a sterile inflammatory reaction. The resulting immune response can impair transplant tolerance or result in acute or chronic graft rejection. In this Review, Braza et al. discuss the nature of DAMPs and their downstream signalling pathways, with a focus on Toll-like receptors. They outline various strategies to inhibit DAMP-induced inflammation with the aim of improving the outcomes of solid organ transplantation, and discuss the challenge of inhibiting the innate immune response within the graft without compromising the patient's response to pathogens.

New data suggest that a fall in parathyroid hormone (PTH) 12 months after initiating haemodialysis is associated with cardiovascular death at 12–24 months. The main independent predictor for the fall in PTH is a high dialysate calcium concentration, which might not only reduce PTH but also induce vascular calcification.

Biological therapeutics that target autoimmune responses have markedly improved the treatment of numerous chronic diseases. In this Review, Stephen Holdsworth and colleagues discuss the opportunities for biologic intervention in autoimmune renal disorders. They outline the key targets that are known to contribute to an injurious inflammatory response, and the biologics that are already available to modulate them.

A new study reports that a single blood test can be used to rule out the development of pre-eclampsia in women in whom the syndrome is suspected. Early interventions for pre-eclampsia are not yet available, but this finding is likely to change the approach to diagnosis of hypertensive disorders in pregnancy.

A recent meta-analysis reports that blood-pressure-lowering treatments reduce the rate of cardiovascular events in patients with baseline systolic blood pressures ranging from >160 mmHg to <130 mmHg. Notwithstanding their diverse data sources, the researchers assert that a blood pressure target of <130 mmHg should be adopted when treating hypertension.

Autoantibodies are produced by plasma cells and contribute to the pathogenesis of many diseases, including systemic or organ-specific autoimmune diseases that involve the kidneys. In contrast to short-lived plasma cells, long-lived plasma cells reside in survival niches in the bone marrow and inflamed tissue, and provide the basis of humoral memory and refractory autoimmune disease activity. Here, the authors discuss the generation of plasma cells, their role in autoimmune disease, and current and future strategies for the depletion of autoreactive plasma cells, including novel approaches that target humoral memory.

Memory T cells and their ability to generate an anamnestic response are vital for protective immunity, but have a potentially detrimental impact on allograft survival. Here, Allan Kirk and colleagues discuss the generation of memory T cells, their role in allograft rejection and therapeutic strategies that target allospecific memory T-cell responses and might improve outcomes in organ transplantation.

Low birth weight (LBW) and intrauterine growth restriction are major contributors to the global burden of non-communicable diseases. A Norwegian registry study has confirmed that LBW is associated with an increased risk of developing end-stage renal disease by 40 years of age, which could not be explained by familial factors.

The unique immunomodulatory properties of multipotent mesenchymal stromal cells (MSCs) make them a promising candidate for cell therapy in organ transplantation. Here, the authors review preclinical data that support the potential tolerance-inducing effects of MSCs in transplant models and the results of initial clinical studies in kidney transplantation.

In this Viewpoint, six leading researchers reflect on progress made in their specialist field of paediatric kidney disease. They provide their insight as to the direction research will take in future years, and comment on areas in which additional research or initiatives are required to improve renal outcomes and patient care for the paediatric and neonatal population.

The SPRINT data suggest a cardiovascular benefit of intensive blood pressure (BP) lowering in high-risk individuals. The BP measurement protocol, however, likely resulted in lower BP values than would normally be obtained in the clinic. Intensive BP targets might not be as safe if routine BP measurements are used.

The development of novel immunotherapies has improved treatment options for several immune-mediated diseases; however, outcomes for patients with immune-mediated kidney disease remain poor. In this Review, Hans-Joachim Anders, David Jayne and Brad Rovin suggest that this lack of progress relates to shortcomings in the approaches used to identify targets and measure outcomes. They discuss seven hurdles to the validation of therapeutic targets in immune-mediated kidney diseases and describe how these hurdles can be overcome to appropriately assess and introduce immunologic therapies for immune-mediated kidney disease.

Healthy mitochondria are essential for normal kidney function and mitochondrial dysfunction has been implicated in various types of renal disorders, both inherited and acquired. In this article, the authors review mitochondrial cytopathies with renal manifestations and the role of mitochondrial dysfunction in acute kidney injury (AKI).

Renal disease is a frequent complication of HIV infection, and a spectrum of renal disorders has been described with diverse histopathologic forms. In this Review, Scott Cohen and colleagues outline the epidemiology of renal disease in HIV and how it has changed since the introduction of combined antiretroviral therapy. They discuss the clinical manifestations and mechanisms underlying renal disease development in patients with HIV, and the issues pertaining to diagnosis and therapeutics.

Genetic studies over the past few years have led to the discovery that a monogenic cause of disease can be detected in ∼20% of individuals with early-onset chronic kidney disease (CKD). In this Review, Vivante and Hildebrandt discuss some of the known single-gene causes of early-onset CKD and the implication of next-generation sequencing for genetic diagnosis. They describe how the discovery of novel causative genes has led to opportunities for delineating the pathomechanisms of disease and potential treatment approaches.