No abstract

and genome-wide association studies identified dachshund homolog 1 (DACH1), which suppresses tubular cell cycle progression, as having protective effects on CKD (7). Though suggestive that ongoing tubular cell cycling may be detrimental, few studies have directly manipulated cell cycle progression in the chronically injured kidney to determine how tubular cell cycle alters tubular injury and fibrosis.Most proximal tubules in the uninjured kidney are quiescent (G0) but, upon injury, reenter the cell cycle at G1, which is the first cell cycle checkpoint. Actively cycling cells progress from G1/S phase (DNA synthesis); then to the second checkpoint, G2; and finally to M (mitosis). Work has established that some tubule cells arrest at G2/M following injury, and these G2-arrested cells play an important role in CKD progression through production of profibrotic growth factors like TGF-β and CTGF (8). However, little is known about the role of cell cycle progression at the G1/S transition in chronically injured tubules. Cyclin dependent kinases 4 and 6 (CDK4/6) combine with cyclin D1 to phosphorylate retinoblastoma protein (Rb), leading to the liberation of E2F, a transcription factor that promotes expression of genes related to G1/S phase progression. The FDA-approved drug palbociclib is a highly selective inhibitor of CDK4/6 that is currently used to treat patients with breast cancer and provides an important tool to assess how G1/S cell cycle progression alters CKD progression.In this manuscript, we use a cell cycle reporter mouse to confirm that cell cycle is persistently altered in the chronically injured proximal tubules. Blocking CDK4/6 in mice after 2 different models of CKD significantly reduced tubular cell cycle progression, ameliorated tubular injury, preserved renal function, and decreased tubulointerstitial fibrosis. Surprisingly, selective tubular deletion of cyclin D1 worsened, rather than improved, tubular injury in murine CKD. Human expression quantitative trait loci (eQTLs) and genome-wide association study (GWAS) data are consistent with the murine studies showing that inhibiting CDK4/6, but not cyclin D1, protects against CKD. Mechanistically, CDK4/6 inhibition reduced proximal tubule cell death through a pathway involving STAT3/IL-1β.

Febuxostat, a new xanthine oxidase (XO) inhibitor, could become the standard for managing uric acid levels in patients with chronic kidney disease (CKD). However, little has been reported regarding patients with severe renal impairment. Further, the conversion rate for switching patients from allopurinol to febuxostat remains unknown. We studied 65 CKD patients being administered allopurinol for hyperuricemia and then switched them to febuxostat at a conversion ratio of 100 mg allopurinol: 10 mg febuxostat. Serum uric acid and creatinine levels were measured before and 4–8 weeks after the switch. Sixty-three patients remained after excluding those who had discontinued treatment. There was no significant difference in serum uric acid and creatinine levels before and after the switch. Further, no significant differences were observed in serum uric acid levels before and after the switch when patients were stratified into diabetic and nondiabetic groups or when classified per gender. We divided patients into G1–G3b and G4–G5 groups depending on the stage of CKD; there were no significant differences in the G1–G3b group after the switch, but there was a significant decrease in serum uric acid levels in the G4–G5 group (p < 0.05). We demonstrated that 100 mg allopurinol and 10 mg febuxostat had equivalent hypouricemic effects in CKD patients and that these drugs did not affect serum creatinine levels. Thus, 10 mg febuxostat may have greater hypouricemic effects in patients with advanced CKD.