Calcineurin inhibitors (CNIs) have a substantial role in maintaining immunosuppression after solid organ transplantation (SOT). These drugs have a narrow therapeutic window, and individual doses and drug treatment monitoring are necessary. Still, a substantial proportion of patients suffer from short- or long-term calcineurin inhibitor toxicity (CNT), including kidney function impairment, hypertension, neurotoxicity, and metabolic disturbances. The authors discuss pathophysiology, clinical presentation, and histological features of CNT, with focus on renal manifestations. Furthermore, we elucidate recent and ongoing attempts to reduce the burden of CNT in SOT including CNI-sparing and CNI-free regimens.

Purpose: Proteinuria is frequent in patients with nephropathies and associated with progressive kidney disease and risk for end stage kidney disease. However, the relevance of deceased donor proteinuria on transplant outcome remains uncertain. In this nationwide cohort study, we evaluated the prevalence of proteinuria in deceased donor candidates and measured the impact on outcome after kidney transplantation. Methods: Data from the Swiss Organ Allocation System and the Swiss TransplantCohort Study were analyzed, comprising 1725 donors and 1516 recipients transplanted between 2008 and 2019. We correlated urine findings with donor characteristics and quantified the impact of proteinuria on allograft function at 12 months and survival.Results: Proteinuria influenced allocation decisions in 4.5% of nonimmunological organ declines and was the leading cause for decline in 0.2% of cases. 74.1%, 51.4%, and 35.3% of donor candidates had a baseline proteinuria above 15, 30, and 50 mg protein/mmol urine creatinine, respectively. Proteinuria above 30 mg/mmol was associated with female donor sex, mechanical resuscitation, acute kidney injury, and time delay between ICU entry and urine sampling. Donor proteinuria was not associated with patient or allograft survival, nor allograft function at 12 months. Conclusion:We report a high prevalence of proteinuria in donor candidates, without evidence of a deleterious impact of proteinuria on graft function and/or survival.Therefore, low-level proteinuria should not be considered a limiting contraindication for kidney allocation in deceased donor transplant.

Background: Calcineurin inhibitors (CNIs) such as cyclosporine A and tacrolimus are commonly used after renal transplantation to suppress the immune system. In lymphoid cells, cyclosporine A acts via the calcineurin/nuclear factor of activated T-cell (NFAT) axis. In non-lymphoid cells, such as kidney epithelial cells, cyclosporine A induces calcineurin inhibitor toxicity. It is unknown via which off-targets cyclosporine A induces calcineurin inhibitor toxicity in kidney epithelial cells.Methods: To measure a compound’s potential to induce nephrotoxicity, the expression of the surrogate marker Fn14 was measured by flow cytometry. Compounds were tested for their potential to induce Fn14 either chemically or plasmid-mediated. Mice were injected with various compounds, and changes in nephrotoxic gene expression levels of the kidney epithelial cells were then analyzed.Results: Fn14 is specifically upregulated due to calcineurin inhibitor toxicity inducing agents. Inhibition of the NFAT axis showed no increase of the Fn14 expression on the surface of kidney cells. However, inhibition of p38 MAPK, phosphoinositide-3-kinase (PI3K)/Akt, protein kinase C (PKC), and inhibitor of nuclear factor-κB (IκB) kinase (IKK) showed clear induction of Fn14 and increased expressions of nephrotoxic, inflammatory, and fibrotic genes in vitro and in vivo.Conclusions: These findings show that cyclosporine A acts independently of NFAT on kidney epithelial cells. Moreover, inhibition of serine/threonine protein kinases mimics cyclosporine A’s activity on kidney epithelial cells. This mimicking effect indicates that these protein kinases are off-targets of cyclosporine A and damage structural renal cells when inhibited and therefore contributes likely to the development and progression of calcineurin inhibitor toxicity.

Summary Kidney transplantation from older and marginal donors is effective to confront organ shortage. However, limitations after transplantation of kidneys from very marginal kidney donors remain unclear. We compared patient and graft outcome, achieved allograft function and quality of life of renal transplantations from Very Senior Donors (VSD, defined as donors aged 70 years and older) with Senior Donors (SD, aged 60–70 years) and Regular Donors (RD, aged younger than 60 years) in Switzerland. We evaluated the outcome of 1554 adult recipients of deceased donor kidney transplantations from 05/2008 to 12/2019; median follow‐up was 4.7 years. Failure‐free survival (freedom from graft loss or death), glomerular filtration rate (eGFR), and quality of life at 12 months were analyzed for RD (reference group, n = 940), SD (n = 404), and VSD (n = 210). Failure‐free survival decreased with increasing donor age, mainly attributable to premature graft loss. Still, overall 5‐year failure‐free survival reached 83.1%, 81.0%, and 64.0% in the RD, SD, and VSD subgroups, respectively. eGFR 12 months post‐transplantation was significantly higher in RD compared with SD and VSD. The acceptance rate of donor candidates for kidney TPL was 78% for the entire cohort (87% for RD, 79% for SD, and 56% for VSD). Deceased donor kidney transplantation from donors aged 70 years or older is associated with an inferior, yet acceptable failure‐free outcome, with sustained quality of life.