Urinary protein excretion exceeding the nephrotic range is associated with a high rate of progression to end-stage renal disease, quality of life worsening, hospitalization, and mortality. Consequently, the achievement of proteinuria reduction represents one of the most important challenges in nephrology.

Proteinuria is recognized as a major and independent risk factor for the progression of renal damage. Steroid-Resistant Nephrotic Syndrome: Has It a Genetic Basis? This review aims at providing an updated description of the pathogenesis, diagnosis, and available therapeutic options for some rare glomerular and tubular kidney diseases, whose molecular basis might be useful in revealing unrecognized and/or unclear causes of steroid-resistant nephrotic syndrome and primary hypertension. Furthermore, this quick and efficient diagnostic tool applied to different renal genetic diseases has recently provided a more accurate characterization of specific genetic and molecular patterns that appear also to be involved in the study of nongenetic and very common renal disorders. The use of high-throughput DNA sequencing technologies appears to be a promising strategy since it permits to obtain a rapid and synchronized analysis of thousands of genes, thus increasing the chance to discover precise disease markers. Generally, each gene involved in a complex disease is responsible only in part for its phenotype and defines simply a “susceptibility” to develop the disorder. In fact, unlike monogenic diseases, complex diseases do not show a classic Mendelian inheritance pattern. Furthermore, the heterogeneous phenotypic manifestations of these diseases suggest an influence of several genetic and environmental determinants. Despite significant therapeutic advances, it is conceivable that there is still much to learn about the pathogenesis of major kidney diseases in order to find more effective and useful therapies in nephrology. The achievement of proteinuria reduction and an optimal blood pressure control are recognized therapeutic goals able to slow CKD progression. Nevertheless, the advent of next-generation sequencing technologies, in recent years, has improved the timing and the quality of the diagnosis of rare kidney diseases, also providing the opportunity to better understand molecular defects shared by both rare and common renal diseases. In most of the cases, however, the diagnosis of a rare kidney disease is still quite difficult and requires considerable experience, and an underestimation of the prevalence of these pathologies might be supposed.

In addition, an understanding of the molecular basis of the defect is important for the development of new targeted therapeutic tools. The early diagnosis and knowledge of the primary cause of a rare disorder are essential for improving the prognosis, especially if therapeutic options are available. In particular, rare kidney diseases are associated with the development of chronic kidney disease (CKD) and its progression to end-stage renal disease, requiring renal function substitution with dialysis or kidney transplantation. Rare diseases are considered a health problem since they are characterized by a high social impact due to the limited knowledge, clinical severity, and restricted therapeutic options associated with them. Key Message: This review deals with the pathogenesis of rare glomerular diseases and tubulopathies associated with hypertension, highlighting the importance of the study of rare diseases to better understand the molecular basis of more common and complex disorders leading to end-stage renal disease. In addition, studies on genetic tubulopathies expressing hypertensive phenotypes can provide useful information for a correct diagnostic and therapeutic approach in patients with essential hypertension and a poor responsiveness to therapy. Summary: In steroid-resistant nephrotic patients, a genetic background has been demonstrated in both children and adults individualized mutations have been correlated with glomerular filtration barrier alterations. To this end, a major contribution may come from the extensive knowledge on the molecular pathways involved in the pathogenesis of rare kidney diseases, since it is now possible to shed light on several aspects of these pathologies thanks to the introduction of new technologies, including next-generation sequencing. Background: The prevention and slowing of chronic kidney disease still represent major challenges in nephrology.

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