Dznep, a histone modification inhibitor, inhibits HIF1α binding to TIMP2 gene and suppresses TIMP2 expression under hypoxia.

Epidemiological studies have shown that patients who recovered from acute kidney injury (AKI) may subsequently develop chronic kidney disease (CKD). AKI is primarily caused by renal hypoxia, and it causes epigenetic alterations, known as hypoxic memory. 3-Deazaneplanocin A (Dznep), an inhibitor of histone modification, suppresses renal fibrosis and the expression of tissue inhibitor of metalloproteinases-2 (TIMP2), a profibrotic factor, in mouse ischemia-reperfusion models. The current study investigated the epigenetic regulation of TIMP2 in human kidney 2 (HK-2) cells. The expression of TIMP2 was upregulated in HK-2 cells under hypoxic conditions and was suppressed by Dznep. ChIP-qPCR showed that Dznep reduced the amount of H3K4me3 at the promoter region of the TIMP2 gene under hypoxic condition. Formaldehyde-assisted isolation of regulatory elements-qPCR of the TIMP2 gene showed that Dznep reduced open chromatin area. In addition, based on ChIP-qPCR of hypoxia-inducible factor 1 alpha (HIF1α), Dznep inhibited the binding of HIF1α to the TIMP2 gene under hypoxic conditions. The reporter assays for the binding region of HIF1α showed enhanced transcriptional activity by hypoxia. Dznep suppresses the expression of TIMP2 under hypoxic conditions by inhibiting the binding of HIF1α to the TIMP2 gene.

Chromatin remodeling factor, INO80, inhibits PMAIP1 in renal tubular cells via exchange of histone variant H2A.Z. for H2A.

Epigenetic modifications such as DNA methylation, histone modifications, and chromatin structures in the kidney contribute towards the progression of chronic kidney disease (CKD). In this study, the role of chromatin remodeling factor inositol requiring 80 (INO80) was investigated. Although INO80 regulates transcription by altering the chromatin structure at the nucleosome level, its role in the kidney remains unknown. We demonstrated that the expression of INO80 in impaired kidneys decreased in rats with unilateral urethral obstruction. We investigated INO80 expression in a proximal tubular cell line and observed that its expression decreased under hypoxic condition. Additionally, INO80 knockdown promoted apoptosis, suggesting that INO80 plays a role in inhibiting tubular cell apoptosis. We identified downstream target genes of INO80 via genome-wide analysis using RNA-sequences and found that the expression of apoptosis-related genes, such as TP53 and E2F1, and pro-apoptotic genes, such as PMAIP1, increased upon INO80 knockdown. ChIP-qPCR of the loci of PMAIP1 showed that the amount of H2A.Z. increased instead of decreasing the amount of H2A when INO80 was knocked down. These results indicated that INO80 plays a role in the exchange of H2A.Z. for H2A in the promoter region of PMAIP1 in tubular cells to inhibit apoptosis during CKD progression.

Treatment of Diabetic Kidney Disease: Current and Future.

Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. However, only renin-angiotensin system inhibitor with multidisciplinary treatments is effective for DKD. In 2019, sodium-glucose cotransporter 2 (SGLT2) inhibitor showed efficacy against DKD in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, adding a new treatment option. However, the progression of DKD has not been completely controlled. The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Furthermore, NF-E2-related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treatment: Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) trial. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights.

Use of Leflunomide as an Antiviral Agent with Everolimus for BK Virus Nephropathy Patients After Kidney Transplantation: A Case Series.

BACKGROUND BK virus nephropathy (BKVN) is the major cause of transplant renal dysfunction. However, a specific antiviral agent to treat it does not exist. One therapeutic option is to reduce use of immunosuppression drugs, which can cause allograft rejection. Leflunomide has both antiviral and immunosuppressive effects, and clinical research has demonstrated its clinical efficacy against BKVN. However, a phase II randomized trial did not support this effect. Therefore, the efficacy of leflunomide remains controversial. CASE REPORT We examined 4 BKVN patients whose Cr levels stabilized with leflunomide therapy. BKVN was confirmed by a kidney biopsy 7-16 months after transplantation. The Cr levels in 3 cases continued to increase after the reduction of immunosuppression drugs, then leflunomide was administered. In 1 case, leflunomide was administered when the immunosuppression drugs were reduced. In all of the cases, mycophenolate mofetil was replaced with everolimus, and tacrolimus was replaced with cyclosporine A. The maintenance doses of leflunomide were 20 mg/day, and leflunomide was used as an antiviral agent for 3 months. In all of the cases, Cr levels and plasma BKV-PCR loads improved after the administration of leflunomide. Renal function was stable without BKVN recurrence or allograft rejection over 3 years after transplantation. CONCLUSIONS Our 4 cases show that short-term use of leflunomide during the active phase of BKVN and a combination of leflunomide and everolimus may be effective against BKVN.

Early Steroid Withdrawal Protocol With Basiliximab and Rituximab in ABO-Incompatible Kidney Transplant Recipients.

OBJECTIVES: Corticosteroids remain an important component of immunosuppressive regimens in high-risk kidney transplants. In this study, we investigated the efficacy of early steroid withdrawal with basiliximab and rituximab in ABO-blood type incompatible (ABO-i) recipients of kidney transplants. METHODS: Between 2008 and 2019, 15 patients underwent ABO-i kidney transplantation. Seven of the 15 patients were treated with a steroid maintenance protocol and the remaining 8 with an early steroid withdrawal protocol. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone (MP), with basiliximab administered as induction therapy. Rituximab was administered as a single 200-mg dose 1 to 4 weeks before kidney transplantation. Two to 4 sessions of either double-filtration plasmapheresis or regular plasmapheresis or both were performed to remove anti-AB antibodies before transplantation. During surgery, MP was administered at a dose of 500 mg; thereafter, the dosage was tapered rapidly, and the drug was discontinued on day 14 post transplant. RESULTS: In the steroid maintenance group, 2 patients experienced acute antibody-mediated rejection (AMR). One patient with severe AMR had graft loss on postoperative day 4. Patient and graft survival rates in the steroid maintenance group were 100% and 86%, respectively. MP was successfully withdrawn in the steroid withdrawal group. In this group, there was no biopsy-proven rejection. Patient and graft survival rates were 100%, and when last measured, serum creatinine level ± SD was 1.6 ± 0.8 mg/dL. CONCLUSIONS: Our protocol successfully enabled the early withdrawal of steroids in recipients of ABO-i grafts; however, further follow-up is necessary to confirm our results.

Successful cadaveric kidney transplantation in an extended-hours hemodialysis patient with long-term hemodialysis vintage for 297 months.

The patient was a 41-year-old male who had been maintained on extended-hours hemodialysis for 297 months. Despite of long-term hemodialysis vintage, he had no vascular calcification and ectopic calcification. His kidney graft did not experience rejection or other complications 18 months after the cadaveric kidney transplant. Previous reports indicated that graft survival of extended-hours hemodialysis patients did not differ from conventional hemodialysis. However, the dialysis periods in these reports were much shorter than our case. Therefore, extended-hours hemodialysis in long-term dialysis patients may improve renal transplant outcomes in the countries where the waiting time for kidney transplant is long.

High low-density lipoprotein cholesterol level is the independent risk factor of primary patency rate of arteriovenous fistula.

OBJECTIVES: An arteriovenous fistula is the first choice of vascular access in dialysis patients. However, the correlations between patient factors and the arteriovenous fistula patency rate remain unclear. Therefore, we examined the effect of dialysis patient factors on arteriovenous fistula patency rate. METHODS: This study included 101 patients who received maintenance dialysis and used arteriovenous fistula for vascular access at Atami Hospital, International University of Health and Welfare in July 2018. A retrospective review was performed from the time of arteriovenous fistula creation to July 2018, and the primary and secondary arteriovenous fistula patency rates were investigated. The patency rate was calculated using the Kaplan-Meier method, and risk factor analysis was performed using Cox proportional hazards regression analysis. RESULTS: The primary patency rate of arteriovenous fistula was 71.2% at one year and 43.0% at five years, and the secondary patency rate was 92.7% at one year and 79.8% at five years. In the multivariate analysis, high low-density lipoprotein cholesterol (LDL-C) level and a history of diabetes were considered significant risk factors (HR 1.023, p value <0.01 and HR 2.550, p value <0.01, respectively). A log rank test was conducted on the groups of patients with LDL <90 mg/dl and LDL ≥90 mg/dl, and the <90 mg/dl group resulted in a good primary patency rate (p value 0.0327). CONCLUSIONS: High LDL-C level was considered the independent risk factors of arteriovenous fistula primary patency rate.