Risk assessment and novel treatment of chronic kidney disease

Abstract

The first chapters of this thesis focus on the prenatal development of the kidney, with a particular focus on the development of a CSFK. We aim to unravel the process of compensatory enlargement in a CSFK. In Chapter 2, a prospective longitudinal study of normal human fetuses is described, focussing on size and growth of the fetal kidney, renal pelvis and adrenal gland. We constructed size charts with multilevel statistical analysis. In Chapter 3, we examinined timing and extent of compensatory enlargement in human fetuses with a CSFK without any other anomaly by comparing CSFK size with charts of normal kidney size. In Chapter 4, we determined glomerular size and volume of pigs with a CSFK with a 3-dimensional stereologic technique and compared this to the nephron volume and size of pigs with two kidneys. Currently, protocol biopsies or crude surrogate markers like longitudinal measurements of the glomerular filtration rate are the only clinical tools available to detect early signs of chronic allograft injury. Therefore, in Chapter 5, we studied the association between urinary CCN-2 levels and renal allograft fibrosis during the first 2 years after transplantation. Histological and biochemical data were collected from 315 kidney transplant recipients enrolled in a protocol biopsy-based clinical program. Emerging evidence also indicates a role for CCN-2 in the pathogenesis of cardiovascular disease. While being expressed only minimally in healthy tissue, CCN-2 is strongly upregulated in atherosclerotic plaques, in cardiac tissue after myocardial infarction, in cardiac fibrosis and in vascular and cardiac tissues in experimental hypertension. In Chapter 6, we investigated the association of plasma CCN-2 with cardiovascular risk and mortality in a high-risk population of patients with manifest atherosclerotic vascular disease. In Chapter 7, we administered microspheres loaded with the mTOR inhibitor rapamycin under the renal capsule and compared this with systemic delivery of rapamycin. In a wide variety of animal models, mTOR inhibitors inhibit interstitial inflammation, fibrosis, and loss of renal function associated with CKD. Although rapamycin has great potential, the use of rapamycin and other mTOR inhibitors is associated with many systemic effects. We hypothesise that a local dose of rapamycin leads to a local therapeutic dose with little systemic consequences and explored the therapeutic potential of this local drug delivery system.