Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.

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In solid organ transplantation lifelong immunosuppression exposes transplant recipients to life-threatening complications, such as infections and malignancies, and to severe side effects. Cellular therapy with mesenchymal stromal cells (MSC) has recently emerged as a promising strategy to regulate anti-donor immune responses, allowing immunosuppressive drug minimization and tolerance induction. In this review we summarize preclinical data on MSC in solid organ transplant models, focusing on potential mechanisms of action of MSC, including down-regulation of effector T-cell response and activation of regulatory pathways. We will also provide an overview of available data on safety and feasibility of MSC therapy in solid organ transplant patients, highlighting the issues that still need to be addressed before establishing MSC as a safe and effective tolerogenic cell therapy in transplantation.