The interaction of S100A16 and GRP78 actives endoplasmic reticulum stress-mediated through the IRE1α/XBP1 pathway in renal tubulointerstitial fibrosis

Recent studies have indicated that the development of acute and chronic kidney disease including renal fibrosis is associated with endoplasmic reticulum (ER) stress. S100 calcium-binding protein 16 (S100A16) as a novel member of the S100 family is involved in kidney disease; however, few studies have examined fibrotic kidneys for a relationship between S100A16 and ER stress. In our previous study, we identified GRP78 as a protein partner of S100A16 in HK-2 cells. Here, we confirmed a physical interaction between GRP78 and S100A16 in HK-2 cells and a markedly increased expression of GRP78 in the kidneys of unilateral ureteral occlusion mice. S100A16 overexpression in HK-2 cells by infection with Lenti-S100A16 also induced upregulation of ER stress markers, including GRP78, p-IRE1α, and XBP1s. Immunofluorescence staining demonstrated that the interaction between S100A16 and GRP78 predominantly occurred in the ER of control HK-2 cells. By contrast, HK-2 cells overexpressing S100A16 showed colocalization of S100A16 and GRP78 mainly in the cytoplasm. Pretreatment with BAPTA-AM, a calcium chelator, blunted the upregulation of renal fibrosis genes and ER stress markers induced by S100A16 overexpression in HK-2 cells and suppressed the cytoplasmic colocalization of GRP78 and S100A16. Co-immunoprecipitation studies suggested a competitive binding between S100A16 and IRE1α with GRP78 in HK-2 cells. Taken together, our findings demonstrate a significant increase in S100A16 expression in the cytoplasm following renal injury. GRP78 then moves into the cytoplasm and binds with S100A16 to promote the release of IRE1α. The subsequent phosphorylation of IRE1α then leads to XBP1 splicing that activates ER stress.

Permanent Ureteral Occlusion

Distal ureteral injuries are uncommon. When present, urine leakage may ensue. Common etiologies are gynecologic surgeries (75%), trauma, pelvic malignancy, and radiation therapy. Clinical presentation varies according to the location of leakage or fistula. For example, patients with ureterovaginal fistula may present with vaginal discharge. Patients with intra-abdominal leakage may develop urinoma or abscess. Unfortunately, most of these patients are poor surgical candidates due to prior surgery and/or radiation. Therefore, operative repair can be challenging and at times not a valid option. Transrenal ureteral occlusion may provide the best available option for such patients. A trial of urine diversion via percutaneous nephrostomy tube may allow spontaneous healing. If this fails, ureteral occlusion proximal to the leak/fistula can be attempted with a success rate up to 100%. Occlusion techniques include ureteral clipping, radiofrequency cauterization, embolization coils, Amplatzer vascular plugs, detachable balloons, absolute alcohol, and isobutyl-2-cyanoacrylate (glue).

Percutaneous Treatment Options of Lower Urinary Tract Fistulas and Leakages

Background Lower urinary tract fistulas are currently a rather rare, but severe condition associated with considerable morbidity. Treatment is challenging, especially in fistulas caused by pelvic malignancy or radiation therapy. Surgical treatment attempts fail in a considerable number of patients, especially in those with pelvic malignancies/prior radiation therapy or are precluded altogether due to severe comorbidity. For such patients percutaneous approaches can provide alternative treatment. Method This review is based on case studies and case reports dealing with percutaneous treatment options of lower urinary tract fistulas and leakages from the past four decades (1979 – 2017). The included techniques were ureteral fulguration, tissue adhesive-based embolization, non-detachable and detachable balloon occlusion, ureteral coiling, ureteral clipping, silicone or nylon plug as well as modified vascular plug embolization. Results and Conclusion Percutaneous treatment options of lower urinary tract fistulas and leakages allow for either permanent or temporary, instant ureteral occlusion. In general, transrenal ureteral occlusion is a safe and reliable alternative to surgical treatment of ureteral fistulas and leakages. So far, no technique has been proven to be superior to the others. Depending on the underlying disease, the optimal percutaneous technique may vary and should be chosen according to the individual needs of the patients. Key Points Citation Format

Therapeutic Ureteral Occlusion with Ifabond Cyanoacrylate Glue: An Interesting Solution

Objective The aim of this study was to present a novel approach for complete and permanent ureteral occlusion using a percutaneous injection of Ifabond cyanoacrylate glue. Methods We describe in detail all the steps of our surgery, performed on a 79-year-old patient with urinary leakage from ureteral stump following radical cystectomy. N-hexyl-cyanoacrylate glue (Ifabond) was used to occlude the distal ureter and solve the leakage. Results Our approach was successful, sparing our already frail patient further surgical procedures. Six months pyelography confirmed the complete ureteral blockage with absence of extravasation. Conclusions In complicated scenarios with urinary leakages and frail patients, synthetic glues such as Ifabond might represent an interesting therapeutic option to solve the fistulas, leading to durable success with a minimally invasive approach.