Despite major improvements in immunosuppressive agents and a reduction in acute rejection episodes, there has been no significant improvement in overall kidney transplant survival beyond the first... Show moreDespite major improvements in immunosuppressive agents and a reduction in acute rejection episodes, there has been no significant improvement in overall kidney transplant survival beyond the first 3 months after transplantation1. Up to sixty percent of all renal allografts are lost within 10 years after transplantation. Apart from death, the main cause of graft loss is chronic allograft nephropathy (CAN)2;3. CAN is characterized by the deterioration of graft function and structure as a consequence of immunological processes (i.e., chronic rejection) and/or a variety of often co-existing non-immunological factors that include: advanced donor age, ischemic injury to the graft during implantation, chronic calcineurin inhibitor induced nephrotoxicity, hypertension, reflux, infection, increased ureteral pressure, and glomerular hyperfiltration. The initial histological characteristics of CAN are the presen ce of tubulointerstitial fibrosis and tubular atrophy (IF/TA)4. Over time, additional features evolve including vasculopathy, glomerulopathy, and glomerulosclerosis. Unfortunately, functional studies significantly underestimate the incidence of graft injury. One of the largest studies with repeated protocol biopsies clearly showed that CAN is a process that develops early after transplantation. Up to 94% of protocol biopsies obtained one year after renal transplantation exhibited IF/TA in patients with stable graft function5. In addition, Solez et al. have shown that 2 years after transplantation two thirds of all kidney allografts exhibit CAN without deterioration of renal function 6. The most significant predictors for the development of CAN were the occurrence of acute rejection episodes, acute calcineurin toxicity, and the initial quality of the transplanted kidney. Often, the first clinical sign of CAN is the progressive decline in renal function as measured by increasing serum creatinine or the development of overt proteinuria2. Although renal function correlates with glomerulosclerosis, unfortunately the clinical tests currently available for renal function are not sensitive enough to detect early lesions associated with CAN. Inulin and iothalamate clearances are more reliable and precise techniques for measuring renal function, but they are expensive, difficult to perform, and time consuming; thus they are unlikely to become routine in daily practice. This situation has given rise to intensified interest in studies using protocol biopsies that may identify surrogate markers and provide insight into the development of CAN. Ideally, a surrogate marker is minimally invasive and amenable to frequent assessment. However, the least invasive markers in blood or urine samples can only identify qualities and quantities of structural lesions i n the renal allograft that typically occur in the advanced stages of disease. Currently, protocol biopsies are considered __the gold standard__ for discovering novel surrogate markers that better predict long-term outcomes for patients. In this thesis, we focused on identifying molecular markers in kidney transplant biopsies that could predict long-term allograft survival. The identification of molecular markers provides a means for superior monitoring of the transplant condition in order to maintain drug efficacy and limit drug-related nephrotoxicity. Moreover, potential new therapeutic targets might be discovered for developing therapies that improve long-term graft survival. Show less
The frequently diagnosed lumbar disc herniation can disappear by natural course, but still leads to high low back surgery rates. The optimal period of conservative care, before surgery is executed,... Show moreThe frequently diagnosed lumbar disc herniation can disappear by natural course, but still leads to high low back surgery rates. The optimal period of conservative care, before surgery is executed, was unknown. It is surprising that scientific evidence was lacking which justified “early” surgery. Surgery, after 6-12 weeks of sciatica, was compared to prolonged conservative care in 283 patients in a randomized study. Primary outcomes were perceived recovery, leg pain intensity and functioning. Early surgery resulted in a 2 times faster recovery rate, compared to prolonged conservative care. From the latter group 39 percent of patients could not evade surgery. Within one year, however, both groups presented similar recovery rates and outcome. The impossibility to sit, because of sciatica, seemed to be a good argument to decide for early surgery. Intense pain and disability were predictors for delayed surgery. Compared to men, females exhibited a 3 times higher odds to develop chronic pain. The higher medical costs of early surgery were fully compensated by quick resumption of working capacity. From a medical point of view one may favor a prolonged wait-and-see strategy but our western society urges patients to decide for early surgery to resume daily activities. Show less
