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
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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.
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