Generation of a conditional cellular senescence model using proximal tubule cells and fibroblasts from human kidneys.

Emerging evidence highlights cellular senescence's pivotal role in chronic kidney disease (CKD). Proximal tubule epithelial cells (PTECs) and fibroblasts are major players in CKD and serve as cellular sources of senescence. The generation of a conditionally immortalized human kidney cell model would allow to better understand the specific mechanisms and factors associated with cellular senescence in a controlled setting, devoid of potential confounding factors such as age and comorbidities. In addition, the availability of human kidney cell lines for preclinical research is sparse and most cell lines do not reflect their in vivo counterparts due to their altered behavior as immortalized cancer-like cells. In this study, PTECs and fibroblasts from human kidneys were isolated and transduced with doxycycline-inducible simian virus 40 large T antigen (SV40LT) vector. By comparing their gene expression with single-cell RNA sequencing data from human kidneys, the newly produced human kidney cell lines demonstrated significant resemblances to their in vivo counterparts. As predicted, PTECs showed functional activity and fibroblasts responded to injury with fibrosis. Withdrawal of the immortalizing factor doxycycline led to p21+ cell-cycle arrest and the key hallmarks of senescence. The obtained senescence gene set largely overlapped between both cell lines and with the previously published SenMayo set of senescence-associated genes. Furthermore, crosstalk experiments showed that senescent PTECs can cause a profibrotic response in fibroblasts by paracrine actions. In 76 human kidney sections, the number of p21+ cells correlated with the degree of fibrosis, age and reduced glomerular filtration, validating the role of senescence in CKD. In conclusion, we provide a novel cellular ex vivo model to study kidney senescence which can serve as a platform for large scale compounds testing.

[Retard chronic kidney disease progression]. / Progressionsbeeinflussung der chronischen Niereninsuffizienz.

Chronic kidney disease (CKD) poses a substantial global health burden. It is classified according to estimated glomerular filtration rate (eGFR) (G1-G5) and albuminuria (A1-A3). In recent years the clinicians' therapeutic options for slowing CKD progression and mitigating cardiovascular disease has been significantly expanded:For CKD with albuminuria, concomitant cardiovascular disease or diabetes mellitus, a target blood pressure <130/80mmHg should be aspired. Apart from the geriatric population and those with a life expectancy below one year a blood pressure <140/90mmHg should be targeted. Renin-angiotensin-system inhibitors (RASi) and sodium-glucose-cotransporter 2 inhibitors (SGLT2i) are the basis of CKD therapy. SGLT2i can be prescribed in most cases of CKD with an eGFR >20ml/min/1.73m2 apart from a few exceptions. Once started, patients should stay on SGLT2i until dialysis. Finerenon is a novel option for diabetic nephropathy with an ACR >30mg/g [3mg/mmol] and an eGFR >25ml/min/1.73m2. Finerenon slows CKD progression and reduces cardiovascular events.

Identifying individuals at risk of needing CKD associated medications in a European kidney disease cohort.

BACKGROUND: The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency. METHODS: Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency. RESULTS: A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%. CONCLUSIONS: In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.