Interactions between the kidney and its environment : chronic intervention studies

Abstract

The aim of this thesis was to investigate the influence of systemic environment on the kidney, and vice versa, in the setting of chronic kidney disease and in the setting of kidney transplantation. Kidney transplantation is known to be the best treatment option for patients with ESKD. The growing difference between decreasing supply of and increasing need for donors led to introducing the marginal living donors as a strategy providing more kidneys for transplants. However, no experimental kidney transplantation model has been described so far where a kidney from marginal living donors (with hypertension background, glomerular damage, etc) is used. Organ shortage demands fundamental research on marginal living donors including accurate predictors of function and injury prior to experimental transplantation. Traditional models of CKD always include uninephrectomy. Avoiding uninephrectomy in ablation models would allow prediction of function and injury at the time-point of experimental transplantation. To this end we developed a novel bilateral renal ablation model that was staged by the level of proteinuria. Chapter 2 gives a detailed description of this model. CKD is characterized by hypertension and concomitant oxidative and inflammatory systemic injury Oxidative damage as such is responsible for hypertension. While the presence of oxidative stress as a feature of CKD is well established, its relation to hypertension and related hemodynamics in established experimental CKD has not been systematically addressed. In Chapter 3 we studied the interaction between oxidative damage and renal hemodynamics in long-term, established experimental CKD. Cardiovascular disease (CVD) is the most common cause of mortality in patients with CKD, having important economical and public health implications. The most common causes of CV death are sudden cardiac death and heart failure which differs from the general population. In Chapter 4 we investigated the underlying mechanisms for enhanced arrhythmogenicity in CKD in two mouse models. The current treatment for CKD is mostly supportive and new therapies are needed. It has been demonstrated that anti-oxidative treatment has little effect on blood pressure and renal hemodynamics in established CKD. Cellbased therapy has proven to be a promising clinical approach for several pathological conditions and might represent a novel strategy to treat kidney disease. These preclinical observations have already translated into pioneering clinical trials. In Chapter 5 we performed a systematic review and meta-analysis to evaluate the efficacy of cell-based therapy in animal studies of CKD, and to determine whether local or systemic factors affect cellbased therapy efficacy. Most cell-based therapy studies used cells or cell products derived from healthy animals. In the clinical situation, however, the use of autologous cells, exposed to the CKD/uremic environment, would be preferred. While administration of healthy bone marrow cells in a rat model of established CKD significantly reduced CKD progression, administration of cells obtained from a rat CKD bone marrow donor had a markedly attenuated effect suggesting a pivotal influence of the diseased environment on the efficiency of the bone marrow cells. Pretreatment of the cells in order to improve their therapeutic efficacy might be useful for developing strategies for cell-based therapies for CKD. In Chapter 6 we aimed to improve the therapeutic efficacy of cells acquired from CKD donors. Ischemia-reperfusion (I/R) is accompanied by an increased mitochondrial production of reactive oxygen species (ROS) and is an inevitable event accompanying kidney transplantation. It is considered a common cause for delayed graft function (DGF) and acute renal failure, ultimately resulting in interstitial fibrosis/tubular atrophy (IF/TA, previously reported as chronic allograft nephropathy). Mechanisms leading to DGF and IF/TA after renal transplantation are poorly understood, and, at present, we lack therapies to prevent I/R injury. In Chapter 7 we studied the early events that accompany kidney transplantation, more specifically the hypoxia associated with IRI and that is preceded damage. Furthermore, we explored whether pre-treatment of the donor (environment) could preserve graft function. This study focuses on the ‘ideal’ kidney transplantation: healthy donor and recipient from the same strain with minimal ischemia time. That is why in Chapter 8 we further explored the kidney graft and environment interaction in the presence of oxidative damage, inflammation, uremia and high blood pressure. We used the bilateral model described in chapter 2 and performed cross transplantation between healthy and CKD donors/recipients. Moreover, we investigated whether the healthy systemic environment could halt the progression of CKD. Cardiac fibrosis with accompanying left ventricular hypertrophy (LVH), can mechanically impede electrical propagation which induces electrical instability leading to arrhythmias and sudden cardiac death. Normalization of hypertension and correction of the uremic state in CKD patients receiving a healthy kidney allograft are known to reverse LVH. However, effects on cardiac fibrosis, a characteristic of CKD, are unknown, as are effects of marginal donor kidneys on recipient LVH and cardiac fibrosis. In Chapter 9 we studied the effect of the healthy or diseased graft (hypertension and uremic state) on left ventricular hypertrophy and cardiac fibrosis in kidney transplantation.