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Item does not contain fulltext, BACKGROUND: RMND1 is a nuclear gene needed for proper function of mitochondria. A pathogenic gene will cause multiple oxidative phosphorylation defects. A renal phenotype consisting of hyponatremia, hyperkalemia, and acidosis is frequently reported, previously considered to be due to aldosterone insensitivity. METHODS: Clinical features and pathophysiology of three patients will be reported. DNA of these patients was subjected to exome screening. RESULTS: In the first family, one pathogenic heterozygous and one highly probable heterozygous mutation were detected. In the second family, a homozygous pathogenic mutation was present. The electrolyte disbalance was not due to aldosterone insensitivity but to low plasma aldosterone concentration, a consequence of low plasma renin activity. This disbalance can be treated. In all three patients, the kidney function declined. In the first family, both children suffered from an unexplained arterial thrombosis with dire consequences. CONCLUSIONS: Hyporeninemic hypoaldosteronism is the mechanism causing the electrolyte disbalance reported in patients with RMND1 mutations, and can be treated., 01 januari 2024

01 april 2023, Contains fulltext : 291123.pdf (Publisher’s version ) (Open Access), RATIONALE & OBJECTIVE: Mono-allelic variants in COL4A3 and COL4A4 (COL4A3/COL4A4) have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic COL4A3/COL4A4 variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic COL4A3/COL4A4 variants identified by whole exome sequencing. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in COL4A3/COL4A4 detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing. RESULTS: Eight different mono-allelic COL4A3/COL4A4 variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure. Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established. LIMITATIONS: Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial

Contains fulltext : 288887.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 247187.pdf (Publisher’s version ) (Open Access)

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Contains fulltext : 217663.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 220207.pdf (publisher's version ) (Open Access)

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Contains fulltext : 193190.pdf (publisher's version ) (Closed access)

01 juli 2017, Contains fulltext : 174487.pdf (Publisher’s version ) (Open Access)

01 juli 2017, Contains fulltext : 174488.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, BACKGROUND/AIMS: Plasma deficiency of pituitary adenylate cyclase-activating polypeptide (PACAP) was recently demonstrated in children with nephrotic syndrome (NS). Previous studies have reported an important protective effect of PACAP on kidney proximal tubules. The aim of this study was to explore the expression of PACAP and its receptors PAC1, VPAC1 and VPAC2 in the healthy and nephrotic kidney and to determine if PACAP has an effect on renal proximal tubular cells exposed to albumin. METHODS: Expression of PACAP and its receptors was studied using kidney tissue from healthy and nephrotic children, and in 3 human renal cell lines (glomerular microvascular endothelial cells, podocytes and proximal tubular epithelial HK-2 cells). The functionality of the VPAC1 receptor was tested in HK-2 cells, measuring cyclic adenosine monophosphate levels after PACAP exposure. The influence of PACAP on cell viability and transforming growth factor-beta1 (TGF-beta1) expression was measured in HK-2 cells exposed to albumin, mimicking proteinuria related damage. RESULTS: VPAC1 expression was detected in the tubular proximal epithelial cells and in the glomerular podocytes of renal tissue from healthy and nephrotic children. Increased staining for PACAP was found in the proximal tubules of renal sections from children with NS compared to healthy renal sections. Expression and functionality of VPAC1 were demonstrated in HK-2 cells. Finally, PACAP did not alter cell viability or TGF-beta1 expression of HK-2 cells exposed to albumin. CONCLUSION: VPAC1 is the predominant receptor in the human kidney. The enhanced presence of PACAP in proximal tubular epithelial cells in nephrotic kidneys points to the reabsorption of filtered PACAP. On short term, PACAP has no in vitro effect on cell viability and TGF-beta1 expression of proximal tubular epithelial cells exposed to high concentrations of albumin.

Contains fulltext : 167821pub.pdf (publisher's version ) (Open Access)

Contains fulltext : 172463.pdf (publisher's version ) (Closed access), Diabetic nephropathy (DN) is the leading cause of CKD in the Western world. Endothelin receptor antagonists have emerged as a novel treatment for DN, but the mechanisms underlying the protective effect remain unknown. We previously showed that both heparanase and endothelin-1 are essential for the development of DN. Here, we further investigated the role of these proteins in DN, and demonstrated that endothelin-1 activates podocytes to release heparanase. Furthermore, conditioned podocyte culture medium increased glomerular transendothelial albumin passage in a heparanase-dependent manner. In mice, podocyte-specific knockout of the endothelin receptor prevented the diabetes-induced increase in glomerular heparanase expression, consequent reduction in heparan sulfate expression and endothelial glycocalyx thickness, and development of proteinuria observed in wild-type counterparts. Our data suggest that in diabetes, endothelin-1 signaling, as occurs in endothelial activation, induces heparanase expression in the podocyte, damage to the glycocalyx, proteinuria, and renal failure. Thus, prevention of these effects may constitute the mechanism of action of endothelin receptor blockers in DN.

Contains fulltext : 172662.pdf (publisher's version ) (Closed access), Heparanase, a heparan sulfate (HS)-specific endoglucuronidase, mediates the onset of proteinuria and renal damage during experimental diabetic nephropathy. Glomerular heparanase expression is increased in most proteinuric diseases. Herein, we evaluated the role of heparanase in two models of experimental glomerulonephritis, being anti-glomerular basement membrane and lipopolysaccharide-induced glomerulonephritis, in wild-type and heparanase-deficient mice. Induction of experimental glomerulonephritis led to an increased heparanase expression in wild-type mice, which was associated with a decreased glomerular expression of a highly sulfated HS domain, and albuminuria. Albuminuria was reduced in the heparanase-deficient mice in both models of experimental glomerulonephritis, which was accompanied by a better renal function and less renal damage. Notably, glomerular HS expression was preserved in the heparanase-deficient mice. Glomerular leukocyte and macrophage influx was reduced in the heparanase-deficient mice, which was accompanied by a reduced expression of both types 1 and 2 helper T-cell cytokines. In vitro, tumor necrosis factor-alpha and lipopolysaccharide directly induced heparanase expression and increased transendothelial albumin passage. Our study shows that heparanase contributes to proteinuria and renal damage in experimental glomerulonephritis by decreasing glomerular HS expression, enhancing renal leukocyte and macrophage influx, and affecting the local cytokine milieu.

Contains fulltext : 170839.pdf (publisher's version ) (Closed access), Proteinuria is one of the first clinical signs of diabetic nephropathy and an independent predictor for the progression to renal failure. Cathepsin L, a lysosomal cysteine protease, can be involved in the development of proteinuria by degradation of proteins that are important for normal podocyte architecture, such as the CD2-associated protein, synaptopodin, and dynamin. Cathepsin L also activates heparanase, a heparan sulfate endoglycosidase previously shown to be crucial for the development of diabetic nephropathy. Here, we evaluated the exact mode of action of cathepsin L in the development of proteinuria in streptozotocin-induced diabetes. Cathepsin L-deficient mice, in contrast to their wild-type littermates, failed to develop albuminuria, mesangial matrix expansion, tubulointerstitial fibrosis, and renal macrophage influx and showed a normal renal function. In wild-type mice the early development of albuminuria correlated with the activation of heparanase and loss of heparan sulfate expression, whereas loss of synaptopodin expression and podocyte damage occurred at a later stage. Thus, cathepsin L is causally involved in the pathogenesis of experimental diabetic nephropathy. Most likely, cathepsin L-dependent heparanase activation is crucial for the development of albuminuria and renal damage.

Contains fulltext : 167162.pdf (publisher's version ) (Closed access), Vitamin D plays an important role in renal (patho)physiology. Patients with glomerular diseases have an injured renal filtration barrier, leading to proteinuria and reduced renal function. An impaired renal function also leads to 1,25-vitamin D3 deficiency as a result of reduced renal 1alpha-hydroxylase activity. Vitamin D treatment to reduce proteinuria remains controversial, although there is an inverse correlation between vitamin D levels and proteinuria. Herein, we showed that 1,25-vitamin D3-deficient 25-hydroxy-vitamin-D3-1alpha-hydroxylase knockout mice and 1,25-vitamin D3-deficient rats develop podocyte injury and renal dysfunction. Glomerular injury was characterized by proteinuria and partial podocyte foot process effacement. Expression of nephrin, podocin, desmin, and transient receptor potential channel C6 in the podocyte was significantly altered in 1,25-vitamin D3-deficient animals. Supplementation with 1,25-vitamin D3 or 1,25-vitamin D2 prevented podocyte effacement or reversed glomerular and tubulointerstitial damage in 1,25-vitamin D3-deficient animals, thereby preserving and restoring renal function, respectively. The effect of 1,25-vitamin D3 deficiency and 1,25-vitamin D3 and 1,25-vitamin D2 repletion on proteinuria could not be explained by hypocalcemia, changes in parathyroid hormone, or fibroblast growth factor 23. This study demonstrates that 1,25-vitamin D3 deficiency directly leads to renal injury in rodents. Translated to human subjects, this would underline the need for early vitamin D supplementation in patients with glomerular disease and chronic renal insufficiency, which might inhibit or potentially reverse renal injury.

Item does not contain fulltext, Regeneration of injured tubular cells occurs after acute tubular necrosis primarily from intrinsic renal cells. This may occur from a pre-existing intratubular stem/progenitor cell population or from any surviving proximal tubular cell. In this study, we characterize a CD24-, CD133-, and vimentin-positive subpopulation of cells scattered throughout the proximal tubule in normal human kidney. Compared to adjacent 'normal' proximal tubular cells, these CD24-positive cells contained less cytoplasm, fewer mitochondria, and no brush border. In addition, 49 marker proteins are described that are expressed within the proximal tubules in a similar scattered pattern. For eight of these markers, we confirmed co-localization with CD24. In human biopsies of patients with acute tubular necrosis (ATN), the number of CD24-positive tubular cells was increased. In both normal human kidneys and the ATN biopsies, around 85% of proliferating cells were CD24-positive - indicating that this cell population participates in tubular regeneration. In healthy rat kidneys, the novel cell subpopulation was absent. However, upon unilateral ureteral obstruction (UUO), the novel cell population was detected in significant amounts in the injured kidney. In summary, in human renal biopsies, the CD24-positive cells represent tubular cells with a deviant phenotype, characterized by a distinct morphology and marker expression. After acute tubular injury, these cells become more numerous. In healthy rat kidneys, these cells are not detectable, whereas after UUO, they appeared de novo - arguing against the notion that these cells represent a pre-existing progenitor cell population. Our data indicate rather that these cells represent transiently dedifferentiated tubular cells involved in regeneration. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Contains fulltext : 97124.pdf (publisher's version ) (Closed access), Total globozoospermia is a rare sperm morphology disorder that consists of 100% round-headed, acrosomeless spermatozoa. There is also a larger group of patients whose sperm cells are partially acrosomeless. The aim of this investigation was to describe partial globozoospermia compared to total globozoospermia and normozoospermia. Ejaculates from 10 patients with more than 50% acrosomeless spermatozoa (partial globozoospermia), 3 patients with total globozoospermia, and 9 normozoospermic controls were analyzed with light microscopy, transmission electron microscopy, and flow cytometry. Qualitative and quantitative examination of spermatozoa from the 3 groups shows differences in the percentage of round-headed sperm cells and acrosome malformation. Total globozoospermia presents as a homogenous kind of teratozoospermia. Partial globozoospermia is a distinctive sperm malformation with an increased proportion of round-headed sperm cells and acrosome malformations compared to normozoospermia, which exists separately from total globozoospermia. It thereby contains oval sperm cells that may have distinctive malformations of the sperm head matrix, but also morphologically normal sperm cells that may be used in a clinical setting.