Reviews & Analysis

Uncertainty exists regarding the optimal timing of initiation of renal replacement therapy in critically ill patients with acute kidney injury in the absence of urgent or life-threatening complications. Two high-profile trials — AKIKI and ELAIN — that aimed to address this issue have recently reported conflicting findings.

Antibodies directed against non-HLA antigens such as angiotensin type 1 receptor, perlecan and collagen have been implicated in antibody-mediated rejection. Here, Elaine Reed and Qiuheng Zhang discuss the clinical relevance and pathogenesis of these non-HLA antibodies in renal, heart and lung transplantation.

Molecular phenotyping of renal biopsy samples from transplant recipients has the potential to improve diagnostic precision and understanding of disease processes. In this Review, Philip Halloran et al. describe their strategy to develop a system that enables the molecular assessment of transplant biopsy samples. They discuss the molecular phenotypes of rejection and injury, and how these studies have improved understanding of the processes that occur in renal transplants over time.

A new study reports an independent association between albuminuria and skin capillary rarefaction in a population-based cohort. These findings suggest that as well as reflecting injury to the glomeruli — a highly specialized microvascular bed — albuminuria might be a surrogate marker of systemic microvascular and endothelial dysfunction.

Antibodies against several podocyte antigens have evolved as markers of diagnosis, disease activity, and prognosis in membranous nephropathy, but their pathogenic role remains debated. Detailed work-up of two cases of primary and secondary membranous nephropathy now supports the concept that thrombospondin type-1 domain-containing 7A autoantibodies are pathogenic.

Time-averaged proteinuria (TAP) is thought to be the most reliable predictor of outcomes in IgA nephropathy (IgAN). New data suggest that corticosteroids reduce TAP and presumably improve outcomes in IgAN, but increase the risk of adverse effects. Whether TAP is a good surrogate end point for clinical trials remains unclear.

The incidence of obesity-related glomerulopathy (ORG) — a distinct entity featuring proteinuria, glomerulomegaly, progressive glomerulosclerosis and renal functional decline — is increasing in parallel with the obesity epidemic. Here, Vivette D'Agati and colleagues review the pathology, clinical features, treatment and pathogenesis of ORG.

The 0by25 Global Snapshot sheds light on the recognition, management and outcomes of acute kidney injury (AKI) in countries worldwide stratified by gross national income. These novel epidemiological data open new horizons for preventing death from AKI particularly in developing countries.

Neutrophils are crucial regulators of the innate immune response and act as a first line of defence against invading microorganisms. To target microorganisms, neutrophils release extracellular structures called neutrophil extracellular traps (NETs), which externalize key autoantigens. In this Review, Gupta and Kaplan explore the contribution of neutrophils and NETs to the pathophysiology of systemic autoimmune disorders that can affect the kidneys, and discuss neutrophils as novel therapeutic targets for these diseases.

The functions of the complement system are diverse and extend beyond its role in host defence; complement activation is now known to contribute to numerous immunological, inflammatory and age-related conditions, including kidney disorders. Here, John Lambris and colleagues discuss the key activating, regulatory, and effector mechanisms of the complement system. They highlight important crosstalk connections with other regulatory systems, and, with a focus on kidney disease and transplantation, describe the involvement of complement in clinical conditions as well as promising therapeutic approaches.

The heterogeneity of pathomechanisms leading to systemic lupus erythematosus (SLE) might contribute to between-patient variations in treatment response. A new, longitudinal transcriptome analysis has identified molecularly distinct subgroups of SLE that correlate with disease activity; use of such disease classifiers might facilitate the development of stratified treatment recommendations.

The calcium-sensing receptor (CaSR) can detect small changes in serum calcium levels and feeds back to modulate parathyroid hormone secretion to elicit appropriate biological responses in different tissues. In this Review, Daniela Riccardi and Giovanna Valenti describe the localization of the CaSR within the nephron and outline its differential functions in different nephron segments. They outline how modulation of the CaSR by pharmacologic approaches could be used in the therapeutic management of disorders such as hyperparathyroidism or hypercalciuric disorders.

Polycystic Kidney disease (PKD) is caused by mutations in genes that affect cilia structure and composition. Impaired mechanosensation through primary cilia has been proposed as a pathogenic mechanism in PKD; however, a new study challenges this hypothesis by showing an absence of mechanically induced Ca²⁺ increases in primary cilia.

Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation. Here, Katalin Susztak and colleagues discuss the reactivation of three key developmental signalling pathways — Notch, Wnt and Hedgehog — in response to injury, and describe the roles of these pathways in the development of renal fibrosis.

LncRNAs are important regulators of kidney and heart morphogenesis and contribute to the development of cardiac disease. Studies over the past 5 years have shown that lncRNAs are also involved in renal diseases such as acute kidney injury, glomerular diseases, acute allograft rejection and renal cell carcinoma. In this Review, Lorenzen and Thum describe current understanding of the function of lncRNAs in renal and cardiovascular diseases and how these non-coding RNAs might be targeted for therapeutic purposes.

The first, highly anticipated randomized trial of adjuvant antiangiogenic therapy in renal cancer was recently reported. Although far from assuring, data from the adjuvant sorafenib or sunitinib for unfavorable renal carcinoma (ASSURE) trial offer a wealth of insights into the disease, treatments, and biological considerations for studies aimed at risk reduction.

Transforming growth factor-β (TGF-β) is a key driver of fibrosis in chronic kidney disease, acting via canonical and non-canonical signalling pathways to activate myofibroblasts and induce the production of extracellular matrix. This Review describes the mechanisms by which TGF-β promotes renal fibrosis, the pathways that modulate TGF-β signalling, and new therapeutic opportunities for the inhibition of TGF-β-driven renal fibrosis

A single-centre study found that desensitization therapy permits a good success rate of kidney transplantation with an incompatible living donor. Data from 22 US centres now suggest that this technique could be employed across multiple hospitals to prolong the lives of sensitized transplant recipients.

Radiologic techniques are routinely used to assess tissue macrostructure and gross morphology. In this Review, Nicolas Grenier and colleagues discuss how technological advancements in CT, MRI, and ultrasonography have faciliated the assessment of organ microstructure and function, and how these techniques can be applied to the kidney. They outline the benefits of incorporating radiologic data with routine clinical diagnostics, and the technical challenges that remain to be addressed when imaging the kidney.

New data demonstrate that caplacizumab treatment accelerates normalization of platelet count in patients with acute episodes of acquired thrombotic thrombocytopenic purpura (TTP). Although not curative, this drug might reduce ischaemic organ damage and be potentially lifesaving for patients with TTP who do not respond to conventional therapy.