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Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that causes thrombocytopenia and a risk of bleeding in the (unborn) child that result from maternal alloantibodies directed against fetal, paternally inherited, human platelet antigens (HPA). It is hypothesized that these alloantibodies can also bind to the placenta, causing placental damage. This study aims to explore signs of antibody-mediated placental damage in FNAIT. We performed a retrospective study that included pregnant women, their newborns, and placentas. It comprised 23 FNAIT cases, of which nine were newly diagnosed (14 samples) and 14 were antenatally treated with intravenous immune globulins (IVIg) (21 samples), and 20 controls, of which 10 had anti-HLA-class I antibodies. Clinical information was collected from medical records. Placental samples were stained for complement activation markers (C1q, C4d, SC5b-9, and mannose-binding lectin) using immunohistochemistry. Histopathology was examined according to the Amsterdam criteria. A higher degree of C4d deposition was present in the newly diagnosed FNAIT cases (10/14 samples), as compared to the IVIg-treated FNAIT cases (2/21 samples, p = 0.002) and anti-HLA-negative controls (3/20 samples, p = 0.006). A histopathological examination showed delayed maturation in four (44%) placentas in the newly diagnosed FNAIT cases, five (36%) in the IVIg-treated FNAIT cases, and one in the controls (NS). C4d deposition at the syncytiotrophoblast was present in combination with low-grade villitis of unknown etiology in three newly diagnosed FNAIT cases that were born SGA. We conclude that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT. This may affect placental function and fetal growth.

Autosomal Dominant polycystic Kidney Disease (ADpKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferatoractivator receptor gamma (ppARγ) agonist pioglitazone slows disease progression in the pcK rat model for pKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPARγ was expressed at surprisingly low levels in mouse, rat and human kidneys. other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow pKD progression. the ongoing phase ii clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADpKD treatment. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, affecting 1 in 2500 individuals 1. The most prominent disease feature is the progressive formation of fluid-filled cysts, mainly in the kidneys and less frequent in liver and pancreas 2. In the majority of patients, the cause of disease is a mutation in the PKD1 (±85%) or PKD2 (±15%) gene, encoding for either polycystin-1 or polycystin-2 3,4. Although the exact mechanisms are not yet completely understood, both PKD1 and PKD2 mutations have been shown to dysregulate many intracellular signalling pathways including mammalian target of rapamycin (mTOR), 5' adenosine monophosphate-activated protein kinase (AMPK), transforming growth factor-beta (TGF-β) and extracellular signal-related kinase (ERK) 5-12. Also, altered fluid secretion involving the cystic fibrosis transmembrane conductance regulator (CFTR) and metabolic alterations (increased glycolysis and reduced fatty acid oxidation) have been reported to contribute to disease progression 13-16. Over the recent years, various interventions based on correcting dysregulated intracellular signalling have been tested in clinical trials 17-21. So far, only the vasopressin V2 receptor antagonist tolvaptan (Jinarc ®), which lowers intracellular cyclic AMP (cAMP) levels in the collecting duct segment of the kidney, was convincingly shown to slow disease progression in patients and is currently available in multiple countries as a treatment option 22-24. While tolvaptan is effective in delaying the loss of renal function, the drug is accompanied by side effects, including polyuria and liver ...

Clusterin, a glycoprotein encoded by the CLU gene, is expressed in many tissues, including the kidney, and clusterin expression is upregulated in the glomeruli of patients with various forms of kidney disease. Here, we investigated the role of clusterin in diabetic nephropathy (DN). In this study, we found that glomerular clusterin expression was increased in both patients with DN and streptozotocin-induced diabetic mice and that it co-localised with the podocyte marker WT1, indicating clusterin is expressed in podocytes. In our in vitro analysis, we found no significant change in CLU mRNA expression in podocytes following stimulation with high glucose and angiotensin II; in contrast, CLU mRNA expression was significantly upregulated following methylglyoxal stimulation. Methylglyoxal treatment also significantly decreased the mRNA expression of the slit diaphragm markers ZO-1 and NEPH1 and significantly increased the mRNA expression of the oxidative stress marker HO-1. Lastly, we showed that pre-incubating podocytes with recombinant human clusterin protein increased podocyte survival, prevented slit diaphragm damage, and reduced oxidative stress‒induced apoptosis following methylglyoxal stimulation. Taken together, our results indicate that glomerular clusterin is upregulated in DN, and this increase in clusterin expression may protect against oxidative stress-induced apoptosis in podocytes, providing a possible new therapeutic target for DN and other kidney diseases.

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