Proteinuria is an independent risk factor for the progression of kidney injury, cardiovascular morbidity, and overall mortality. In this thesis, the pathways leading to proteinuria are explored by... Show moreProteinuria is an independent risk factor for the progression of kidney injury, cardiovascular morbidity, and overall mortality. In this thesis, the pathways leading to proteinuria are explored by revisiting elements previously considered essential, investigating known pathways, and identifying new players in the field of proteinuria. First, a zebrafish embryo model for developing new therapeutic options for the rare but devastating disease of nephropathic cystinosis is presented. The studies presented in thesis also investigate loss of heparan sulphate glycosaminoglycans in a zebrafish embryo model and in multiple osteochondroma patients. These studies show that loss of heparan sulphate glycosaminoglycans does not always lead to proteinuria. Next, dynamin is described as a promising potential therapeutic target for treating proteinuria. The final study introduces transmembrane protein 14A as an essential factor in maintaining glomerular filtration barrier function. Overall, these studies contribute to elucidating the pathways to proteinuria in the hope to keep advancing the field towards targeted treatment of proteinuria for the benefit of our patients. Show less
In this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial... Show moreIn this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans. A case report of a patient with an EXT1 mutation indicated that this could result in a specific renal phenotype. This patient suffered from multiple osteochondromas, an autosomal dominant disease caused by mono-allelic germline mutations in the EXT1 or EXT2 gene. These studies imply that HS is indeed essential to the glomerular filtration barrier. However, loss of HS did not lead to proteinuria in various animal models. We demonstrate that multiple osteochondroma patients do not have more microalbuminuria or altered glycocalyx properties compared to age-matched controls (n = 19). A search for all Dutch patients registered with both osteochondroma and kidney biopsy (n = 39) showed that an EXT1 or EXT2 mutation does not necessarily lead to specific glomerular morphological phenotypic changes. In conclusion, this study shows that a heterozygous mutation in the HS backbone elongating enzymes EXT1 and EXT2 in humans does not result in (micro)albuminuria, a specific renal phenotype or changes to the endothelial glycocalyx, adding to the growing knowledge on the role of EXT1 and EXT2 genes in pathophysiology. Show less
Matrix metalloproteinases (MMPs) may play a pathophysiological role in the development of diabetic nephropathy (DN). We hypothesized that urinary MMP activity in patients with type 2 diabetes... Show moreMatrix metalloproteinases (MMPs) may play a pathophysiological role in the development of diabetic nephropathy (DN). We hypothesized that urinary MMP activity in patients with type 2 diabetes mellitus (T2DM) is related to a decline in renal function. We determined MMP-2, -8 and -9 activity in 24-h urine collections in relation to risk factors for ON in T2DM patients with (UA, n=27) and without albuminuria (NA, n=48) and controls (CO, n=28). MMP-8 and -9 levels were highest in UA patients (P<0.01). Of UA patients, 93% had at least one MMP increased, compared to 78% of NA patients and 46% of CO (P=0.001). Age, diabetes duration, BMI, systolic blood pressure, fasting plasma glucose, HbA1c and renal function were determinants of MMP-8 and -9 (P<0.05). In summary, MMP-8 and -9 are highest in T2DM UA patients. MMP-9, showed the strongest associations with clinical parameters related to DN. (C) 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Show less
This thesis focuses on the incidence and risk factors for nephropathy in diabetic and non-diabetic Surinamese South Asians. The Surinamese South Asians, originally descended from the North-East... Show moreThis thesis focuses on the incidence and risk factors for nephropathy in diabetic and non-diabetic Surinamese South Asians. The Surinamese South Asians, originally descended from the North-East India. Due to the former colonial bounds with the Netherlands, a relatively young South Asian migrant population settled in the Netherlands. South Asians have a high prevalence of central obesity and an eight-fold higher prevalence for type 2 diabetes mellitus. We found the following conclusions: 1.Surinamese South Asian persons have a nearly 40-fold higher risk for end-stage diabetic nephropathy in comparison to Dutch European persons. 2.There was no familial predisposition for diabetic nephropathy among South Asian families. 3.South Asian type 2 diabetic patients have a three-fold higher risk for diabetic nephropathy and faster progression of renal insufficiency in comparison to Dutch European patients. 4.Central obesity is an early and independent risk factor for increased albuminuria in normoglycemic South Asian subjects. We assume that the nearly 40-fold higher risk of end-stage diabetic nephropathy in South Asian migrants is primarily caused by central obesity which leads to: a. Early renal injury in the pre-diabetic state. b. Eight-times higher prevalence of type 2 diabetes mellitus. b. More diabetic nephropathy and faster decline in renal function. Show less
