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Since publication of the first issue of Nature Reviews Nephrology 20 years ago, advances across various subspecialities of nephrology have provided insights into disease processes and led to the development of new therapeutics for people with kidney disease. However, despite this progress, many kidney diseases remain untreatable, the costs of kidney disease care are immense, and vast inequities persist in disease burden and access to care. In this Viewpoint, we ask experts from several key subspecialties of nephrology to reflect on progress made over the past 20 years, remaining challenges and the steps needed to move the field forward.

The theme of World Kidney Day 2024 is “kidney health for all — advancing equitable access to care and optimal medication practice”. To mark this event, Nature Reviews Nephrology invited five researchers from different geographical regions worldwide to discuss the impact of new and emerging therapies for diabetic kidney disease on patient care as well as the barriers that must be overcome to ensure equitable access to these therapies.

When tested in a multiethnic cohort of ~2.5 million US veterans, the PREVENT equations, recently developed by the American Heart Association for sex-specific and race-free prediction of cardiovascular disease risk, were shown to accurately estimate this risk with some variability across race and ethnicity groups and to outperform the previously used pooled cohort equation risk score.

The accumulation of alpha-synuclein fibrils within neurons is the defining feature of Lewy body dementia (LBD). Here the authors report a method to produce large quantities of alpha-synuclein fibrils that reproduce the complex structure of the fibrils that accumulate in LBD brain tissue.

A mouse model of Down syndrome (DS) highlights the importance of triplication of the IFNR gene cluster for a variety of DS-associated traits. Copy number correction resulted in amelioration of multiple phenotypes associated with the condition.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

Glutathione has pleiotropic functions in different organs. Here the authors specifically examine deletion of a glutathione synthetic enzyme in the liver of adult mice and show that lack of glutathione affects lipid abundance through repressing NRF2.

In a prespecified analysis of the FLOW trial, the use of an SGLT2 inhibitor did not impact the overall benefits of semaglutide on kidney and cardiovascular outcomes in participants with type 2 diabetes and chronic kidney disease.

In a pre-specified secondary analysis of the SELECT trial, once-weekly subcutaneous semaglutide 2.4 mg in patients with obesity was associated with a 22% reduction in the main 5-component kidney composite endpoint compared to patients on placebo.

Down syndrome (DS) is caused by trisomy 21 (T21), but the underlying etiology of the related immune and neurological dysfunction is unclear. Here, the authors show that T21 activates the kynurenine pathway via increased interferon receptor copy number, which could contribute to DS pathophysiology.

After nearly two decades, a new therapeutic agent, canagliflozin, received regulatory approval to prevent loss of kidney function, end-stage kidney disease, hospitalization for heart failure and cardiovascular death in patients with diabetic kidney disease. Nonetheless, the residual risk of kidney disease progression and complications remains high, underlining the importance of ongoing therapeutic development.

The COVID-19 pandemic has placed a tremendous strain on sustaining the clinical research enterprise and will also likely affect key study outcomes; these effects must be considered during data analysis and interpretation. Nevertheless, the responses to the pandemic have also introduced innovations that will advance the conduct of clinical research.

A high-resolution kidney cellular atlas of 51 main cell types, including rare and previously undescribed cell populations, represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

The escalating burden of diabetic nephropathy is largely a function of the increased frequency of type 2 diabetes, which is associated with obesity and the metabolic syndrome. Prevention is dependent on elucidation of causal mechanisms. Here, Richard Johnson and colleagues present evidence for a mechanism that might form the basis of novel intervention strategies.

Clinical trials have demonstrated that glucagon-like peptide 1 receptor (GLP1R) agonists have therapeutic benefits beyond glycaemic control. Here, the authors examine the protective effects of incretin-based therapies in patients with diabetic kidney disease and how the immunomodulatory and anti-inflammatory effects of GLP1 might underlie this protection.

Several new drug classes have been demonstrated to improve kidney outcomes in people with diabetes mellitus. Here, the authors examine the evidence for the efficacy and safety of combination treatment to reduce the progression of diabetic kidney disease.

Despite notable progress in basic, clinical and translational nephrology research in the past 50 years, many challenges remain. In this Review, the authors provide an overview of the current status and future directions in nephrology research and patient care.

This Review examines the concept of kidney lifespan and how increases in haemodynamic and metabolic demands in the kidney can lead to nephron overload, which is a common feature of progressive kidney disease and therefore represents a therapeutic target.

A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal—including 131 previously uncharacterized species—from the Zoonomia Project provides data that support biological discovery, medical research and conservation.

Tissue cytometry is a promising new microscopy technique that can be used to enumerate and characterize each cell in a tissue. Here the authors describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues.

Lutnick et al. develop a cloud-based deep learning tool for whole slide image segmentation. The authors provide several examples of its application in renal pathology, for segmenting glomeruli, interstitial fibrosis and other features of interest.