In this thesis, two potential therapeutic targets for diabetic nephropathy were dentified and investigated. First, we show that glomerular clusterin is upregulated in diabetic nephropathy and... Show moreIn this thesis, two potential therapeutic targets for diabetic nephropathy were dentified and investigated. First, we show that glomerular clusterin is upregulated in diabetic nephropathy and demonstrated that recombinant clusterin protein can protect the podocytes against oxidative stress in vitro. Second, we reveal that hCN1 overexpression accelerated and aggravated diabetic nephropathy in BTBR ob/ob mice. We also studied two novel zebrafish models to investigate chronic kidney disease. We showed that lepb-/- adult zebrafish have the early signs of human diabetic nephropathy, and we demonstrated that ctns mutant adult zebrafish have the kidney pathologic features of human nephropathic cystinosis. Show less
Aims We aimed to compare renal sinus fat volume assessed by MRI between patients with type 2 diabetes and healthy volunteers, and investigate the association between renal sinus fat and metabolic... Show moreAims We aimed to compare renal sinus fat volume assessed by MRI between patients with type 2 diabetes and healthy volunteers, and investigate the association between renal sinus fat and metabolic traits.Methods In this cross-sectional study, renal sinus fat and parenchyma volumes measured on abdominal MRI were compared between patients and controls using analysis of covariance. Associations of renal parameters with clinical characteristics were analyzed using linear regression analysis.Results A total of 146 participants were enrolled, consisting of 95 type 2 diabetes patients (57.2 +/- 8.8 years, 49.5% male) and 51 controls (54.0 +/- 9.2 years, 43.1% male). Patients with diabetes demonstrated larger sinus fat volumes (15.4 +/- 7.5 cm(3) vs. 10.3 +/- 7.1 cm(3), p < 0.001) and sinus fat-parenchyma ratio than controls. In the total population, renal sinus fat was positively associated with HbA1c, abdominal VAT, cholesterol and triglycerides, after adjustment for age, sex, ethnicity and type 2 diabetes. In type 2 diabetes patients, increased sinus fat volume was significantly associated with urinary albumin-to-creatinine ratio.Conclusion Renal sinus fat volume is positively associated with several metabolic risk factors including HbA1c level and urinary albumin-to-creatinine ratio in type 2 diabetes patients, indicating a potential role of renal sinus fat in the development of diabetic nephropathy. Future studies are needed to investigate whether sinus fat volume can serve as an early biomarker for diabetic nephropathy. Show less
Patients with diabetes mellitus have the highest mortality risk within the dialysis population. The presence of chronic kidney disease (CKD) in patients with diabetes is also strongly related to... Show morePatients with diabetes mellitus have the highest mortality risk within the dialysis population. The presence of chronic kidney disease (CKD) in patients with diabetes is also strongly related to impaired quality of life. Research is warranted to prevent progressive diabetic kidney disease, improve quality of life and reduce mortality in this vulnerable population. In order to improve survival, more knowledge about which patients have the highest mortality risk and which risk factors and co-morbid conditions contribute to this increased mortality risk is essential. In this thesis we focussed on clinical aspects of the relation between diabetes mellitus and kidney disease, from hyperfiltration to dialysis. In chapter 2 we assessed many different measures of glucose metabolism and their association with kidney function among Dutch middle-aged adults. In chapter three and four we compared survival of dialysis patients with diabetes mellitus as underlying cause of the renal failure versus dialysis patients with diabetes mellitus as a co-morbid condition only. In chapter five we aimed to develop a prediction model for 1-year mortality in diabetic dialysis patients. Furthermore in chapter six we compared survival after amputation in diabetic dialysis patients to non-diabetic dialysis patients. Show less
The endothelial glycocalyx (EG) is critically involved in vascular integrity and homeostasis, where it regulates endothelial cell mechanotransduction, vascular permeability, coagulation and... Show moreThe endothelial glycocalyx (EG) is critically involved in vascular integrity and homeostasis, where it regulates endothelial cell mechanotransduction, vascular permeability, coagulation and inflammation. Loss of the glomerular EG component, hyaluronan, results in albuminuria and vascular destabilisation. Glomerular loss of hyaluronan has a profound effect on endothelial stability, and similar effects were observed in tumor vessels of metastatic melanomas and in muscular tissue of diabetic patients with critical limb ischemia. Endothelial hyaluronan biosynthesis is critically determined by the endothelial metabolic state which glycolysis is a determining factor of endothelial hyaluronan biosynthesis and function. Show less
Smith, A.; Iablokov, V.; Mazza, M.; Guarnerio, S.; Denti, V.; Ivanova, M.; ... ; Magni, F. 2020
Introduction: Diabetic nephropathy (DN) and hypertensive nephrosclerosis (HN) represent the most common causes of chronic kidney disease (CKD) and many patients progress to -end-stage renal disease... Show moreIntroduction: Diabetic nephropathy (DN) and hypertensive nephrosclerosis (HN) represent the most common causes of chronic kidney disease (CKD) and many patients progress to -end-stage renal disease. Patients are treated primarily through the management of cardiovas-cular risk factors and hypertension; however patients with HN have a more favorable outcome. A noninvasive clinical approach to separate these two entities, especially in hypertensive patients who also have diabetes, would allow for targeted treatment and more appropriate resource allocation to those patients at the highest risk of CKD progression. Meth-ods: In this preliminary study, high-spatial-resolution matrix-assisted laser desorption/ion-ization (MALDI) mass spectrometry imaging (MSI) was integrated with high-mass accuracy MALDI-FTICR-MS and nLC-ESI-MS/MS analysis in order to detect tissue proteins within kidney biopsies to discriminate cases of DN (n = 9) from cases of HN (n = 9). Results: Differences in the tryptic peptide profiles of the 2 groups could clearly be detected, with these becoming even more evident in the more severe histological classes, even if this was not evident with routine histology. In particular, 4 putative proteins were detected and had a higher signal intensity within regions of DN tissue with extensive sclerosis or fibrosis. Among these, 2 proteins (PGRMC1 and CO3) had a signal intensity that increased at the latter stages of the disease and may be associated with progression. Discussion/Conclusion: This preliminary study represents a valuable starting point for a future study employing a larger cohort of patients to develop sensitive and specific protein biomarkers that could reliably differentiate between diabetic and hypertensive causes of CKD to allow for improved diagnosis, fewer biopsy procedures, and refined treatment approaches for clinicians. Show less
In this thesis, the involvement of the complement system was studied in various diseases that affect the microvasculature of the kidney. We focused on the clinicopathologic significance of... Show moreIn this thesis, the involvement of the complement system was studied in various diseases that affect the microvasculature of the kidney. We focused on the clinicopathologic significance of complement deposits along the renal microvasculature of patients with thrombotic microangiopathy, a disorder that is characterized by severe endothelial injury and microvascular thrombosis; IgA nephropathy and IgA vasculitis with nephritis, auto-immune disorders that can cause microvascular injury in adults and children; transplant glomerulopathy, an important cause of late graft dysfunction and renal allograft loss; preeclampsia, a leading cause of maternal and perinatal morbidity and mortality; and diabetic nephropathy, a microvascular complication of diabetes mellitus and a leading cause of end-stage renal disease. Special attention was paid to C4d, a cleavage product of C4 activation, which is commonly used as a biomarker for complement activation. Our data suggest that the complement system is involved in the pathogenesis of various renal microangiopathies and that complement activation along the microvasculature may contribute to disease progression in a subset of patients. Our findings may contribute to the development of improved diagnostic workup, new therapeutic strategies and patient-tailored therapy. Show less
Simultaneous pancreas-kidney transplant is the ultimate therapy for patients who have uncontrolled and complicated type 1 diabetes mellitus with end-stage renal disease. The combined pancreas... Show moreSimultaneous pancreas-kidney transplant is the ultimate therapy for patients who have uncontrolled and complicated type 1 diabetes mellitus with end-stage renal disease. The combined pancreas transplant provides a euglycemic milieu for the kidney and protects it from recurrence of diabetic complications. Our patient, a 41-year-old woman with end-stage diabetic nephropathy and history of multiple abdominal surgeries (ovarian cyst fenestration, adnexal extirpation, abdominal wall reconstruction), including urinary diversion (Bricker loop, above double J stent), underwent simultaneous pancreas-kidney transplant. After reperfusion, the kidney had immediate function and creatinine levels dropped to normal levels during the early postoperative period (creatinine of 102 mu mol/L, estimated glomerular filtration rate of 52 mL/min/1.73 m(2)) and remained stable during follow-up. Serum glucose levels dropped to within normal ranges postoperatively and remained so during follow-up. The postoperative course was complicated by hydronephrosis due to transient edema of the anastomosis of the ureter to the Bricker loop, after early incidental removal of the double J catheter. This was successfully treated with a temporary percutaneous nephrostomy. Multiple previous surgeries, including a Bricker deviation, may not be a definitive contraindication for simultaneous pancreas-kidney transplant. In selected cases, special considerations may lead to a successful procedure providing better quality of life and life expectancy, even for patients with multiple comorbidities. Show less
Diabetic nephropathy is a major cause of end-stage renal disease worldwide. In this thesis we investigated several aspects of diabetic nephropathy, including histological lesions scored... Show moreDiabetic nephropathy is a major cause of end-stage renal disease worldwide. In this thesis we investigated several aspects of diabetic nephropathy, including histological lesions scored according to the pathologic classification of diabetic nephropathy, inflammatory markers, the CNDP1 gene and the carnosine metabolism. Several studies of this thesis used histological and clinical data obtained from an autopsy cohort of patients with diabetes. The renal tissue of this autopsy cohort provided us with the opportunity to investigate more than 100 glomeruli per case and gave us the opportunity to challenge several hypotheses in a unique setup. Show less
Bus, P.; Scharpfenecker, M.; Wilk, P. van der; Wolterbeek, R.; Bruijn, J.A.; Baelde, H.J. 2017
Conclusions/interpretation Taken together, circulating MBL levels are associated with diabetic nephropathy and are dependent on glycaemic control, possibly in an MBL2-genotype-dependent manner.
Peters, V.; Klessens, C.Q.F.; Baelde, H.J.; Singler, B.; Veraar, K.A.M.; Zutinic, A.; ... ; Heer, E. de 2015
My thesis concerns different aspects of diabetic nephropathy. A pathologic classification of diabetic nephropathy is developed, a meta-analyis of genes in diabetic nephropathy is developed and the... Show moreMy thesis concerns different aspects of diabetic nephropathy. A pathologic classification of diabetic nephropathy is developed, a meta-analyis of genes in diabetic nephropathy is developed and the other chapters are about the CNDP1 gene in relation to kidney disease, mainly diabetic nephropathy. Show less
Zijl, N.J. van der; Hanemaaijer, L.; Tushuizen, M.E.; Schindhelm, R.K.; Boerop, J.; Rustemeijer, C.; ... ; Diamant, M. 2010
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
