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.

Hematophagous leeches rely on a broad diversity of bioactive factors that interfere with the host’s defense systems to secure a successful blood meal. The most prominent examples of such factors are the antithrombotics that address either the primary hemostasis (the platelet aggregation) or the secondary hemostasis (the blood coagulation). Whereas the inhibitors of platelet aggregation mainly cause continuous blood flow, coagulation inhibitors mainly keep the blood fluid within the stomach of the leech. The critical dependency of hematophagous leeches on the accurate action of all antithrombotic factors may explain the presence of multiple genes for each type of these factors that is regularly observed in leech genomes. The genome of Hirudinaria manillensis Lesson, 1842, the Asian buffalo leech, contains five individual genes that encode variants of the coagulation inhibitor hirudin. However, no genes that encode putative decorsins, the archetype of leech-derived inhibitors of platelet aggregation, have been described to date. Here, we report the identification of one monomeric and four multimeric decorsin encoding genes in the genome of H. manillensis. A selection of the putative decorsins was expressed as recombinant proteins, purified and functionally characterized. All but one of these putative decorsins displayed platelet aggregation-inhibitory potencies. Furthermore, we provide a mathematical calculation based on the mechanism of alternative pre-mRNA splicing that illustrates the potential to generate an enormous variety of different factors from one single multimeric ornatin gene.

Medicinal leeches express a broad variety of anticoagulants and other bioactive factors that are involved in the blood feeding process. For most of the anticoagulants, several genes exist that may encode isoforms of the respective proteins, including hirudins and decorsins. Decorsins negatively affect platelet aggregation, whereas hirudins are potent thrombin inhibitors. Both factors belong to the hirudin superfamily that also includes the group of hirudin-like factors, and all hematophagous leeches analyzed so far contain several gene copies that encode representatives of at least two of the three groups of these factors. Members of the hirudin superfamily may contain only one central globular domain, but others may contain two or more copies. Here we describe the molecular identification and partial functional characterization of a broad variety of putative mono-, bi and multimeric hirudins, decorsins and hirudin-like factors in two Asian medicinal leech species, namely Hirudo nipponia and H. tianjinensis . Some of the monomeric hirudins and decorsins have already been described before, but they represent only a small part of the overall diversity. For the first time, putative monomeric and one oligomeric decorsins of H. tianjinensis were expressed as recombinant proteins, functionally characterized and successfully verified as platelet aggregation inhibitors. In addition we have conducted phylogenetic analyses based on genomic and mitochondrial markers and found convincing evidence that H. nipponia and H. tianjinensis together with members of the genus Whitmania form a monophyletic clade that is clearly distinct from clades that are formed either by European members of the genus Hirudo or by members of the genus Hirudinaria .

Leeches of the genus Placobdella Blanchard, 1893 (Annelida: Rhynchobdellida: Glossiphoniidae) are mainly distributed across North and Central America, but at least two species are also present in the palearctic region: the European turtle leech Placobdella costata Müller, 1846, and the North African turtle leech Placobdella nabeulensis Ben Ahmed et al., 2023. All species of the genus are hematophagous and feed on vertebrates, but are known to preferentially target aquatic and semi-aquatic reptiles like turtles and snakes. Placobdella ornata Verrill, 1872, is the original source of ornatins, a class of potent platelet aggregation inhibitors. However, the whole repertoire of bioactive peptides, including anticoagulation factors remains largely underexplored for Placobdella , and functional characterizations of putative antithrombotics are scarce. Here we describe the genes and cDNAs that encode putative hirudins and ornatins in both of the palearctic and three American species of the genus Placobdella . A selection of putative hirudins and ornatins was recombinantly expressed and functionally characterized using appropriate coagulation and platelet aggregation assays, and our data confirm the expression of functional hirudins and ornatins in the studied leeches. In addition, our genetic analyses strongly support the hypothesis that blood feeding evolved only once in the evolutionary history of leeches.