The incidence rate of AKI in hospitalized patients is increasing. However, relatively little attention has been paid to the association of AKI with long-term risk of adverse coronary events. Our study investigated hospitalized patients who recovered from de novo dialysis-requiring AKI between 1999 and 2008 using patient data collected from inpatient claims from Taiwan National Health Insurance. We used Cox regression with time-varying covariates to adjust for subsequent CKD and ESRD after discharge. Results were further validated by analysis of a prospectively constructed database. Among 17,106 acute dialysis patients who were discharged, 4869 patients recovered from dialysis-requiring AKI (AKI recovery group) and were matched with 4869 patients without AKI (non-AKI group). The incidence rates of coronary events were 19.8 and 10.3 per 1000 person-years in the AKI recovery and non-AKI groups, respectively. AKI recovery associated with higher risk of coronary events (hazard ratio [HR], 1.67; 95% confidence interval [95% CI], 1.36 to 2.04) and all-cause mortality (HR, 1.67; 95% CI, 1.57 to 1.79) independent of the effects of subsequent progression to CKD and ESRD. The risk levels of de novo coronary events after hospital discharge were similar in patients with diabetes alone and patients with AKI alone (P=0.23). Our results reveal that AKI with recovery associated with higher long-term risks of coronary events and death in this cohort, suggesting that AKI may identify patients with high risk of future coronary events. Enhanced postdischarge follow-up of renal function of patients who have recovered from temporary dialysis may be warranted.

The Krüppel-associated box A (KRAB-A) domain is an evolutionarily conserved transcriptional repressor domain present in approximately one-third of zinc finger proteins of the Cys ₂ -His ₂ type. Using the yeast two-hybrid system, we report the isolation of a cDNA encoding a novel murine protein, KRAB-A interacting protein 1 (KRIP-1) that physically interacts with the KRAB-A region. KRIP-1 is a member of the RBCC subfamily of the RING finger, or Cys ₃ HisCys ₄ , family of zinc binding proteins whose other members are known to play important roles in differentiation, oncogenesis, and signal transduction. The KRIP-1 protein has high homology to TIF1, a putative modulator of ligand-dependent activation function of nuclear receptors. A 3.5-kb mRNA for KRIP-1 is ubiquitously expressed among all adult mouse tissues studied. When a GAL4–KRIP-1 fusion protein is expressed in COS cells with a chloramphenicol acetyltransferase reporter construct with five GAL4 binding sites, there is dose-dependent repression of transcription. Thus, KRIP-1 interacts with the KRAB-A region of C ₂ H ₂ zinc finger proteins and may mediate or modulate KRAB-A transcriptional repressor activity.

Pericytes have been identified as the major source of precursors of scar-producing myofibroblasts during kidney fibrosis. The underlying mechanisms triggering pericyte-myofibroblast transition are poorly understood. Transforming growth factor β-1 (TGF-β1) is well recognized as a pluripotent cytokine that drives organ fibrosis. We investigated the role of TGF-β1 in inducing profibrotic signaling from epithelial cells to activate pericyte-myofibroblast transition. Increased expression of TGF-β1 was detected predominantly in injured epithelium after unilateral ureteral obstruction, whereas downstream signaling from the TGF-β1 receptor increased in both injured epithelium and pericytes. In mice with ureteral obstruction that were treated with the pan anti-TGF-β antibody (1D11) or TGF-β receptor type I inhibitor (SB431542), kidney pericyte-myofibroblast transition was blunted. The consequence was marked attenuation of fibrosis. In addition, epithelial cell cycle G2/M arrest and production of profibrotic cytokines were both attenuated. Although TGF-β1 alone did not trigger pericyte proliferation in vitro, it robustly induced α smooth muscle actin (α-SMA). In cultured kidney epithelial cells, TGF-β1 stimulated G2/M arrest and production of profibrotic cytokines that had the capacity to stimulate proliferation and transition of pericytes to myofibroblasts. In conclusion, this study identified a novel link between injured epithelium and pericyte-myofibroblast transition through TGF-β1 during kidney fibrosis.