Reviews & Analysis

The year 2015 has seen great progress in the renal fibrosis field, as key studies began to build a consensus on the importance of epithelial-to-mesenchymal transition, cell cycle arrest, and defective metabolism in the pathogenesis of kidney fibrosis. New findings also point to a role of developmental signalling in renal fibrogenesis.

The effects of SGLT2 inhibitors on lowering blood pressure are well characterized, but data now demonstrate their enhanced blood pressure-lowering capacity when combined with dual antihypertensive therapy. Specifically, blood pressure was markedly reduced when dapagliflozin was administered to patients receiving a renin–angiotensin system blocker plus a calcium antagonist or β-blocker.

A relationship between IgA nephropathy (IgAN) and the mucosa has long been recognized with evidence from clinical observations and genetic studies suggesting that abnormalities in the IgA mucosal immune system could be a key element in the pathogenesis of IgAN. In this Review, Jürgen Floege and John Feehally describe current evidence that links the mucosa, in particular the gastrointestinal mucosa, and IgA produced in the bone marrow with IgAN.

2015 saw the publication of several important studies in the renal stem cell and developmental biology fields. Key studies provided insights into the ageing of nephron progenitors and optimal conditions to stimulate the expansion of nephron progenitors, and reported the in vitro generation of kidney organoids.

Podocyte biologists can boast of some important advances in 2015. Some of the key developments include defining the transcriptional targets of the Wilms' tumour protein on a genome-wide scale, the identification of new mitochondria-centred pathways for maintaining podocyte homeostasis, and new insights into the regulation and pathogenic activation of TRPC6.

Blockade of the renin–angiotensin–aldosterone system (RAAS) slows the progression of many forms of kidney disease, but whether this therapy is beneficial in kidney transplant recipients is unclear. A new randomized controlled trial suggests that RAAS blockade is not beneficial in the transplant setting, but the underpowered nature of this study limits its conclusions.

Combination therapy with optimal doses of multiple antihypertensive drugs fails to achieve blood pressure (BP) control in up to 15% of hypertensive patients. Key studies in 2015 highlighted the risks of uncontrolled hypertension and evaluated new therapeutic modalities designed to achieve satisfactory BP control in patients with treatment-resistant hypertension.

Numerous studies in 2015 focused on therapeutic immune modulation and immunosuppression. Trials of budenoside in patients with IgA nephropathy who are unresponsive to supportive therapy, and of low-dose IL-2 to enforce regulatory T-cell-mediated immunosuppression in autoimmune disease all produced promising results.

Renal anaemia, resulting from impaired renal production of erythropoietin, is a common occurrence in patients with chronic kidney disease. Conventional erythropoiesis stimulating agents can be used to treat the condition, but small-molecule inhibitors of prolyl hydroxylase domain-containing (PHD) enzymes might provide a more efficient and tolerable approach to anaemia management. Here, Maxwell and Eckardt describe the rationale for targeting PHD enzymes to increase erythropoietin production. They also discuss other potential on-target consequences of HIF activation and possible off-target effects on enzymes that are structurally similar to PHD enzymes.

Renal transplantation can be successfully performed in patients of all ages, and the short-term and medium-term outcomes have improved over the past decades. In this Review, Christer Holmberg and Hannu Jalanko discuss the long-term effects of kidney transplantation on paediatric recipients. They outline the adverse effects that can occur with regard to growth, bone health, metabolic and cardiovascular complications, and malignancies, and highlight the challenges that remain in managing the care of paediatric renal transplant recipients.

A recent subanalysis of data from the PEGASUS-TIMI 54 trial indicates a favourable balance between the efficacy and safety of ticagrelor in patients with prior myocardial infarction (MI), irrespective of their renal function. These results support the long-term use of ticagrelor in patients with chronic kidney disease and prior MI.

Over the past decade remote ischaemic preconditioning (RIPC) has evolved as a promising strategy to reduce ischaemia in remote organs. Although previous studies using surrogate outcomes have encouraged further investigation, two recent randomized controlled trials — the ERICCA trial and the RIPHeart Study — were unable to detect a protective effect of RIPC.

A close relationship has been described between cardiometabolic disorders (CMDs) and the gut microbiota. In this Review, Judith Aron-Wisnewsky and Karine Clément outline the evidence supporting a link between the composition of the gut microbiota with cardiovascular and chronic kidney disease. They outline the methods used to study the microbiome, the effect of dietary intake patterns on microbiota composition and its derived metabolites, and possible areas for intervention to prevent or treat CMDs.

Treatment of hepatitis C virus (HCV) infection in patients with chronic kidney disease (CKD) can be challenging. Now, data from the phase III C-SURFER study show that grazoprevir and elbasvir — a new all-oral combination therapy for HCV — is safe and effective in patients with stage 4–5 CKD.

Fluid therapy with saline is considered by some to confer a notable risk of acute kidney injury and mortality. However, data from the SPLIT trial — the first large, randomized controlled trial to compare saline to a 'balanced' solution — do not indicate any marked signal of harm in critically ill patients.

In the past decade considerable advances have been made in understanding the physiology and pathophysiology of coagulation proteases, their regulators and receptors in renal disease. In this Review, Berend Isermann and colleagues discuss the haemostatic and non-haemostatic functions of coagulation regulators and receptors in the kidney, the roles of coagulation proteases in acute kidney injury, chronic kidney disease and renal transplantation, and the potential for translating these insights into targeted therapies.

Hypertension is an important risk factor for cardiovascular and renal disease; however, despite the availability of several antihypertensive drug classes only about half of patients with treated hypertension achieve appropriate blood pressure control. This Review describes the potential of pharmacogenomics and other 'omics' approaches to identify genetic signals to predict an individual's response to a particular drug and enable a more personalized, or precision approach to antihypertensive treatment strategies.

A new study reports that B7-1 is not expressed on the podocytes of patients or mice with diabetic nephropathy. In contrast to the findings of some previous studies, these data suggest that targeting B7-1 on podocytes using abatacept might not be an appropriate therapeutic strategy for diabetic renal disease.

Pattern recognition receptors and danger-associated molecular patterns of the innate immune system contribute to the initiation of an inflammatory response in diabetes mellitus and diabetic nephropathy. In this Review, Jun Wada and Hirofumi Makino discuss how these components of the innate immune system can lead to insulin resistance, diabetes mellitus, and renal failure and describe signalling mediators and pathways that could be targeted for treatment.

Renal involvement in primary Sjögren syndrome (pSS) is a rare complication, but regular screening is required for early detection and prevention of progression to chronic kidney disease. In this Review, Hélène François and Xavier Mariette discuss the most frequent renal complications that can occur in pSS, namely tubulointerstitial nephritis and membranoproliferative glomerular nephritis. They outline the pathophysiology of these complications, the differential diagnoses, and current treatment options.