**5. Summary**

**1.** Replicative senescence pathways ARF-p53-p21 (associated with telomere shortening).

as telomere shortening can be bypassed by transfection with telomerase [25].

nucleus and its function as a transcription factor.

188 Current Issues and Future Direction in Kidney Transplantation

cell division, as was demonstrated by Melk *et al* [25]*.*

or cellular age [28].

regenerative capacity [29].

Telomeres comprise tandem TTAGGG repeats of 5000 to 15000 base pairs that normally reside at the ends of chromosome ends as protection and prevent end-to-end fusion of chromosomes. Telomeric DNA is synthesized and its length is regulated by telomerase. Most somatic cells don't express telomerase and mature telomeres tend to progressively shorten with every cell division. The crucial role of telomerase absence in the telomere shortening is proven *in vitro*

Telomere length reflects several important factors such as heredity, telomerase activity, the efficiency of telomere-binding proteins, the rate of cellular proliferation and oxidative stress in the milieu. Although telomere length is partly heritable, there are major differences in telomere length even among monozygotic twins, which suggests that environmental factors (e.g. hyperglycemie, oxidative stress [26, 27]) play a major role in telomere attrition and aging. When the telomeres become critically short (reach the "Hayflick limit") a classical DNAdamage response is triggered with participation of several protein kinases (e.g. ATM and CHK2), adaptor proteins (e.g. 53BP1 and MDC1) and chromatin modifiers (e.g. gammaH2AX). Telomere shortening also leads to activation of the p53 pathway (trough p53 phosphorylation) and herewith associated p21 (also termed CDKN1a, p21Cip1, Waf1 or SD11) expression. Also other DNA damage responses (DDRs) and ARF (alternate reading frame, p14) can lead to activation of the p53 pathway. SIRT1 (sirtuin 1) can negatively regulate p53 localization to the

The clinical importance of telomere shortening has been suggested in a very interesting study, where leukocyte telomere length was used as a biomarker of aging. In this study, the associ‐ ation between telomere length and various disease processes was independent of chronolog‐ ical age, which suggests the value of telomere length measurement as a biomarker of biological

In contrast to, e.g. blood cells, the association between age and telomere shortening in renal tissue was only studied scarcely. The supposed association with reduced regenerative capacity during aging and chronic diseases, and after acute injury, seems valid but has never been proven in humans. Only Westhoff 's study in telomerase deficient mice suggests that critical telomere shortening in kidneys leads to increased senescence and apoptosis, thereby limiting

In adult kidneys, telomerase activity is very low, which results in telomere shortening by every

shortening as has been shown in different animal models [30-32] Finally, glomerular diseases like IgA nephropathy, lupus nephritis and focal glomerulosclerosis are associated with increased p53 expression compared to kidneys without lesions, both in animals [33] and in

After bone marrow transplantation telomere shortening occurs significantly more rapidly than would be expected in graft-derived leukocytes. Probably due to the replicative stress on the blood cell caused the kinetics of haemopoietic engraftment [36]. After solid organ transplan‐ tation there are arguments to state that transplantation is associated with accelerated short‐ ening of telomere length in the transplanted cells [12]. In transplanted renal cells, there is

humans [34, 35] Whether this relates to telomere length has not been studied to date.

. Also ischemia can induce telomere

In summary, there is extensive data that the outcome of kidney transplantation is heavily influenced by the age of the transplanted kidneys. There is some scant evidence that trans‐ plantation in itself increases cell turnover and leads to accelerate replicative senescence. Whether the association between older kidneys and impaired graft outcome relates to this accelerate replicative senescence after transplantation is however not clear, and the few suggestions in the literature need to be validated in large-enough patient cohorts.
