Reconstruction of the urinary tract at the appropriate time reduces fibrosis of the metanephros in rats as judged by imaging

Abstract

22Chronic kidney disease leads to high morbidity rates among humans. It is a 23 serious disease that requires curative treatments other than kidney transplantation. 24 Recently, we successfully established the iPS-derived generated kidney, which might 25 produce urine. The urine can be directed to the native bladder with a stepwise peristaltic 26 ureter system, followed by anastomosis with the recipient ureter for reconstruction of 27 the urinary tract. However, the growth of the regenerated kidney varies significantly, 28 whereas the time window of the anastomosis is quite narrow. Therefore, this study was 29 conducted to evaluate the growth of transplanted metanephros with bladder periodically 30 and noninvasively using computed tomography and ultrasonography. Ultrasonographic 31 findings showed high correlations with computed tomographic findings and clearly 32 evaluated metanephros with bladder. We found that the degree of growth of the 33 metanephros with bladder after the transplantation differed in each individual. However, 34 most of them reached the appropriate period for urinary tract reconstruction within 3 35 weeks after transplantation. Optimizing the stepwise peristaltic ureter system 36 anastomosis by ultrasonography reduced long-term tubular dilation of the metanephros, 37 thereby decreasing fibrosis caused by transforming growth factor-β. This may be 38 significantly related to long-term maturation of fetal grafts. These results provide new 4 39 insights into transplanting regenerated kidneys in higher animals. We are one step closer 40 to the first human trial of kidney generation. 41 42 6 74provide a route for excretion of the produced urine. Thus, metanephros can cause 75 hydronephrosis and renal insufficiency [11,12]. This may be solved using Stepwise 76 Peristaltic Ureter (SWPU), which (S1 Fig.) comprises anastomosis of the ureters of the 77 recipient rats to the bladder using a developed metanephros with bladder (MNB) [11]. 78 This new method made it possible to continuously excrete urine produced from the 79 MNB to the recipient bladder via the recipient ureter [11]. However, the timing of 80 anastomosis with the ureter of the recipient after transplantation is crucial and owing to 81 individual differences in the growth of MNB, hydronephrosis may occur at ambiguous 82 anastomosis times [11,13]. Postrenal nephropathy due to hydronephrosis imposes a 83 heavy burden on the kidneys, and the delayed release of obstruction has substantial 84 effects on the kidneys [14-16]. Ureteral primordia obstruction during the fetal stage has 85 been shown to cause dysplastic metanephros [17]. Therefore, we believe that early 86 released obstruction is significantly involved in subsequent renal functions, even with 87 fetal-derived grafts. In the case of xenotransplantation and MNB transplantation in large 88 experimental animals, the effects of individual differences are considered to be greater.89 Appropriate time must be allowed for urinary tract reconstruction using a minimally 90 invasive method ...