The nephrotic syndrome holds significant clinical importance and is characterized by a substantial protein loss in the urine. Damage to the glomerular basement membrane or podocytes frequently underlies renal protein loss. There is an increasing belief in the involvement of the complement system, a part of the innate immune system, in these conditions. Understanding the interactions between the complement system and glomerular structures continually evolves, challenging the traditional view of the blood–urine barrier as a passive filter. Clinical studies suggest that a precise inhibition of the complement system at various points may soon become feasible. However, a thorough understanding of current knowledge is imperative for planning future therapies in nephrotic glomerular diseases such as membranous glomerulopathy, membranoproliferative glomerulonephritis, lupus nephritis, focal segmental glomerulosclerosis, and minimal change disease. This review provides an overview of the complement system, its interactions with glomerular structures, and insights into specific glomerular diseases exhibiting a nephrotic course. Additionally, we explore new diagnostic tools and future therapeutic approaches.

At the beginning of life, there are no sex differences in fetal kidney growth, nephron endowment nor in the prevalence of low birth weight. In chronic kidney disease (CKD) in adults, however, significant sex- and gender-specific differences exist in diagnosis, progression, and management of CKD. In adult individuals, CKD is more prevalent in women, but CKD progression is faster in men; nevertheless, women have a higher life expectancy than men. A possible explanation for the enigmatic higher CKD prevalence in women may derive from the Brenner–Luyckx concept of hyperfiltration. Diseases that lead to hyperfiltration will lead to premature nephron loss and to a faster decline in glomerular filtration rate (GFR). This condition is predominantly seen in middle-aged men with a higher GFR, larger hypertrophied kidneys, and a higher prevalence of arterial hypertension, diabetes mellitus, smoking, and hypercholesterolemia compared to women. Thus, a high GFR may not be a good sign if it reflects hyperfiltration. Any GFR must be interpreted against the comorbidities of an individual. An individual may end up with a realistic GFR far below normal once hyperfiltration is stopped, for example, by a Sodium Glucose-Linked Transporter 2 (SGLT2) inhibitor. With regard to the management of CKD, women with CKD receive poorer healthcare compared to men with CKD. Women less frequently receive a CKD diagnosis, are less frequently referred to nephrology for co-management, less frequently undergo eGFR and albuminuria assessments, and are less likely to receive guideline-recommended treatments for CKD, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and statins. Cardiovascular risk factors are less rigorously controlled in women with CKD compared to men with CKD. The causes for the poorer CKD care among women are to be found in gender rather than in sex. It is crucial to integrate assessments of sex and gender into both clinical routines and scientific reports. All studies should incorporate sex- and gender-specific analyses, and the evaluation of pre- and postmenopausal women should be conducted separately. The utilization of Gender Scores can help identify the impact of cultural, societal, and psychological factors on observed gender differences in ambulatory healthcare for those with CKD. Guidelines need to be sensitive to gender and emphasize the existing knowledge gaps regarding sex and gender differences in CKD healthcare. Urgent attention is required to substantially improve and ensure equitable healthcare for CKD across sexes and genders.

Chronic kidney disease (CKD) is a major global health burden leading to a loss of kidney function via podocyte damage, a non-regenerative renal cell type. Early detection of podocyte injury is crucial but remains limited, highlighting the need for non-invasive biomarkers. Therefore, we analysed urinary exosomal microRNAs (miRNAs) in relation to podocyte morphology in biopsies from 65 CKD patients, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD) and healthy controls. Global profiling distinguished CKD patients from controls, with miR-606 consistently upregulated and miR-431 downregulated. In podocytopathies, MCD displayed a predominantly suppressed miRNA profile, with miR-141, miR-429, and miR-660 as key candidates, whereas FSGS exhibited elevated miR-181c, miR-3610, miR-663b, miR-4651, and miR-429. Super-resolution morphometry revealed diffuse foot process effacement in MCD and heterogeneous, focally disrupted architecture in FSGS, providing a structural context for the molecular findings. Regression analyses linked these miRNAs to filtration slit density and length, proteinuria, and 25-Hydroxy-vitamin-D3 levels, integrating molecular, structural, and clinical readouts. These results define a coherent miRNA signature of podocyte injury that distinguishes CKD entities and correlates molecular changes with disease severity. Combining urinary exosomal miRNAs with morphometric analysis facilitates early, non-invasive identification of podocyte damage, enabling earlier therapeutic intervention in podocytopathies.