*4.4. CKD-*/*ESKD Treatment-Associated Ageing (Dialysis, Transplantation)*

As the uremic milieu associates with premature ageing and senescence, one could speculate that RRT (dialysis and renal transplantation [Rtx]) improves a prematurely aged phenotype. However, the dialysis procedure itself exerts pro-inflammatory and pro-oxidative e ffects due to multiple factors, such as bio-incompatibility of dialysis membranes or fluids, contaminated/polluted dialysis water, intravenous iron treatment, activation of the renin–angiotensin–aldosterone system (RAAS), and depletion of anti-oxidants [6] potentially resulting in adverse e ffects on ageing processes in RRT. Ageing-associated phenotypes are also observed after Rtx. Thus, patients undergoing Rtx have an increased risk for complications, including ischemia-reperfusion injury (IRI) and allograft rejection during and after Rtx. These complications can result in an accelerated senescence as assessed by p21Waf1/Cip1 and p<sup>16</sup>Ink4a, as well as telomere shortening [127]. Furthermore, transplant biopsies show strong p16INK4a staining beyond the amount predicted by chronological age [142]. Conversely, short-term inhibition of the senescence promoter p53 reduces IRI-induced senescence and improves kidney outcome in mice [143]. Immunosuppressive treatment of the recipients can further result in therapy-induced senescent cells that remain in the transplanted kidney and mediate adverse pro-ageing signals [144]. Thus, patients receiving mycophenolate mofetil after Rtx have an increased telomere attrition compared to azathioprine-treated patients, supporting a direct e ffect of immunosuppressive treatment on ageing [145]. Taken together, RRT by either dialysis or Rtx does not arrest ageing processes, and RRT might even accelerate the ageing phenotype.

### **5. Approaches for Handling of Inflammation and Premature Ageing in CKD**

Inflammation and premature ageing are hallmarks in the pathogenesis of CKD and its many complications, having highly detrimental e ffects on health status, quality of life, and mortality. However, current treatment recommendations indicate that each single risk factor for CKD progression and its complications must be treated separately and, at the final stage, RRT has to be provided [42]. This approach led to substantial improvements in reducing example, in patients with T1D, the use of novel insulins, new glucose monitoring devices, and the widespread usage of RAAS blockers has improved the outcome [146,147]. However, because the global burden of disease due to CKD is increasing [148], systemic approaches for the treatment of CKD and its complications are warranted to target the underlying hallmarks of CKD, that is, inflammation and premature ageing. Some of these are summarized below.
