Focal segmental glomerulosclerosis (FSGS) is a heterogeneous renal histopathological entity that affects the glomerulus. It is characterized by podocyte injury, proteinuria and scarring of the... Show moreFocal segmental glomerulosclerosis (FSGS) is a heterogeneous renal histopathological entity that affects the glomerulus. It is characterized by podocyte injury, proteinuria and scarring of the glomerular tuft. In this thesis we investigated various mechanisms that are implicated in the development of FSGS. Firstly, we studied biopsy samples of patients with minimal change disease, a related glomerulopathy with minimal glomerular injury and better prognosis. We showed that loss of nephrin could serve as a biomarker for renal function loss and the progression to FSGS in this patient group. We also investigated renal biopsy material of patients with FSGS to determine the role of complement activation and endothelial-podocyte interaction in the pathogenesis of FSGS. We show that complement activation via the classical pathway and endothelial injury, especially via endothelin-1 signaling, are associated with the development of FSGS in humans. This thesis also describes the study of the genomic architecture of the Munich Wistar Frömter rat model for FSGS, which led to the prioritization of TMEM63c and PTGR2 in the development of podocyte injury and proteinuria in this model. The identification of these mechanisms in the development of FSGS, increases our understanding of the pathophysiology of FSGS and can guide future studies into new, highly needed therapeutic strategies. Show less
Duijl, T.T. van; Ruhaak, R.; Hoogeveen, E.; Mutsert, R. de; Rosendaal, F.; Cessie, S. le; ... ; Cobbaert, C. 2022
Background and aims: There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins NGAL, IGFBP7, TIMP2, KIM-1, CXCL9, TGF-beta 1,... Show moreBackground and aims: There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins NGAL, IGFBP7, TIMP2, KIM-1, CXCL9, TGF-beta 1, SLC22A2, nephrin, cubilin and uromodulin have been proposed as early kidney injury biomarkers. To guide clinical interpretation, their urinary concentrations should be accompanied by reference intervals, which we here establish in a representative Dutch middle-aged population. Materials and Methods: The 24-h urine samples from 1443 Caucasian middle-aged men and women, were analyzed for the biomarkers by quantitative LC-MS/MS. Biomarker excretion per 24-h were calculated, and urine creatinine and osmolality were measured for dilution normalization. This population was characterized by demographic and anthropometric parameters, comorbid conditions, and conventional kidney function measures. Results: NGAL, IGFBP7, TIMP2, KIM-1 and uromodulin could be quantified in this population, whereas nephrin, SLC22A2 and CXCL9 were below their detection limits. Urine creatinine and osmolality ( r= -were correlated to urine volume (r = -0.71; -0.74) and to IGFBP7 (r = 0.73; 0.71) and TIMP2 (r = 0.71; 0.69). Crude and normalized biomarker concentrations were affected by sex, but not by age, BMI, smoking, kidney function or common comorbid conditions. The reference intervals (men; women) were 18-108; 21-131 pmol IGFBP7/mmol creatinine, 1- 63; 4-224 pmol NGAL/mmol creatinine, 7-48; 7- 59 pmol TIMP2/mmol creatinine, <1-9; <1-12 pmol KIM-1/mmol creatinine and 0.1-1.2; 0.1-1.7 mg uromodulin/mmol creatinine. Conclusion: We present dilution-normalized and sex-stratified urinary reference intervals of kidney injury biomarkers in a middle-aged Caucasian population. Show less
Several cellular processes and pathways were altered both by fluid shear stress and Pkd1 gene disruption in renal epithelial cells. Many of these signaling pathways are implicated in ADPKD as... Show moreSeveral cellular processes and pathways were altered both by fluid shear stress and Pkd1 gene disruption in renal epithelial cells. Many of these signaling pathways are implicated in ADPKD as well. However, more than 20 years after the discovery of PKD1 and PKD2 as genetic cause of ADPKD, the exact cellular function of the polycystins still remains unclear. Our data indicate that polycystin-1 is not a direct mechano-sensor, but it restrains shear stress induced gene expression via an unknown mechanism. Additional research is required to identify the cellular function of polycystins and the mechanism of mechanotransduction. This is needed to refine the mechanism of cyst formation in ADPKD and other ciliopathies, which could identify potential targets for therapy. Nevertheless, we showed that inhibition of activin signaling is a promising therapy to slow cyst progression in Pkd1del mice. Although other treatment strategies have been tested successfully to reduce PKD progression in pre-clinical studies, the efficacy in human patients is sometimes minimal or absent. Therefore, it has been suggested to target multiple signaling pathways affected in ADPKD. These combined therapies should reestablish the balance in cellular signaling of renal epithelial cells and maintain cellular homeostasis within physiological boundaries. Show less
This dissertation aimed to identify opportunities to slow down disease progression and improve health-related quality of life (HRQOL) in patients with chronic kidney disease (CKD). Biopsychosocial,... Show moreThis dissertation aimed to identify opportunities to slow down disease progression and improve health-related quality of life (HRQOL) in patients with chronic kidney disease (CKD). Biopsychosocial, patient-centred and self-regulation perspectives were employed and enabled this dissertation to shed light on the importance of patients’ health behaviours and illness perceptions in the treatment of CKD. Taken together, this dissertation indicates that patients in early CKD stages are in need of behavioural support to cope with the broad range of barriers that they experience when reducing sodium intake. The results demonstrate that a multicomponent patient-centred self-regulation program would fit patients' needs, and can reduce risk factors for disease progression and improve psychosocial outcomes. Furthermore, this dissertation suggests that support strategies should be implemented to increase the impaired HRQOL that many patients experience during predialysis care. The results underline the need for personalized treatment approaches in light of the differences between patients in relation to their HRQOL and how their HRQOL evolves over time (e.g., differences with regard to age and cardiovascular disease). Moreover, illness perceptions were found to be key factors in HRQOL and disease progression, and therefore, treatment strategies in predialysis care should take into account patients’ illness perceptions as well. Show less
Endothelial injury and repair are most important concepts for our understanding of renal disease and allograft injury. The concept that injury to the endothelium may precede renal fibrosis strongly... Show moreEndothelial injury and repair are most important concepts for our understanding of renal disease and allograft injury. The concept that injury to the endothelium may precede renal fibrosis strongly suggests that interventions to maintain vascular integrity are of major importance for renal function. This thesis focuses on the mechanisms involved in the process of endothelial damage and repair in renal disease, (early) diabetes mellitus (DM) and renal ischemia-reperfusion (I/R) injury. Furthermore, microvascular alterations were assessed, using sidestream darkfield (SDF) imaging and measurement of endothelial dysfunction markers (including angiopoietins), in chronic kidney disease (CKD) and DM patients before and after (pancreas) kidney transplantation. The results of this thesis demonstrate an important role for endothelial damage and repair in renal disease and after transplantation. Both renal I/R and DM induced systemic capillary damage reflected by increased capillary tortuosity by SDF imaging and a dysbalance in angiopoietins. In addition, patients with CKD and allograft rejection after renal transplantation also had systemic microvascular derangements. Transplantation was effective in reversing the systemic microvascular alterations. Complementary use of SDF imaging to measure microvascular tortuosity and the assessment of endothelial dysfunction markers may be useful diagnostic tool for monitoring the microvasculature before and after transplantation. Show less
The clinical course of renal diseases depends on the type of renal disorder, genetic factors, environmental influences, and the severity of renal fibrosis. Proteinuria is the abnormal amount of... Show moreThe clinical course of renal diseases depends on the type of renal disorder, genetic factors, environmental influences, and the severity of renal fibrosis. Proteinuria is the abnormal amount of proteins present in the urine. Proteinuria is an independent risk factor for development of renal insufficiency, in which glomerulosclerosis can be seen in biopsies. Experimental models described in this thesis show that different genetic factors are linked to proteinuria and glomerulosclerosis. Furthermore, bone marrow and kidney transplantations between proteinuria-prone and proteinuria-resistant rats, revealed that both renal and bone marrow-derived cells contribute to development of proteinuria or convey resistance to its development. The mechanism of development of segmental glomerulosclerosis is not completely known. We investigated glomerular morphology in hyperfiltration-mediated proteinuria before glomerulosclerosis was present. Segmental glomerulosclerosis started with segmental podocyte damage with loss of podoplanin protein. Focal and segmental glomerulosclerosis is a human renal disease with a wide range of glomerular morphology, a large range of clinical presentations, progression rates, and chances of developing recurrent FGSG after transplantation. A new histological classification was proposed in 2004 in hopes of separating new disease subentities. We found that in most cases FSGS recurred as the same variant, supporting the new classification. The results in this thesis may increase the insights in the development of proteinuria and glomerulosclerosis, hoping to result in earlier recognition of renal disease, better definition of patients and separation of distinct disease entities. This may lead to better and more disease-specific treatment options. Show less
