Increasing renal mass improves survival in anephric rats following metanephros transplantation

Abstract

Renal failure and end-stage renal disease are prevalent diseases associated with high levels of morbidity and mortality, the preferred treatment for which is kidney transplantation. However, the gulf between supply and demand for kidneys remains high and is growing every year. A potential alternative to the transplantation of mature adult kidneys is the transplantation of the developing renal primordium, the metanephros. It has been shown previously, in rodent models, that transplantation of a metanephros can provide renal function capable of prolonging survival in anephric animals. The aim of the present study was to determine whether increasing the mass of transplanted tissue can prolong survival further. Embryonic day 15 rat metanephroi were transplanted into the peritoneum of anaesthetized adult rat recipients. Twenty-one days later, the transplanted metanephroi were anastomosed to the recipient's urinary system, and 35 days following anastomosis the animal's native renal mass was removed. Survival times and composition of the excreted fluid were determined. Rats with single metanephros transplants survived 29 h longer than anephric controls (P < 0.001); animals with two metanephroi survived 44 h longer (P < 0.001). A dilute urine was formed, with low concentrations of sodium, potassium and urea; potassium and urea concentrations were elevated in terminal serum samples, but sodium concentration and osmolality were comparable to control values. These data show that survival time is proportional to the mass of functional renal tissue. While transplanted metanephroi cannot currently provide life-sustaining renal function, this approach may have therapeutic benefit in the future.

Urine excretion strategy for stem cell-generated embryonic kidneys

“…Previous studies described the direct connection of a recipient ureter with the ureter of a transplant-grown metanephros (uretero-ureterostomy) to create a urine excretion channel for a neokidney (Fig. S1B) (11)(12)(13), prolonging the short-term survival of anephric rats (12,13). However, our SWPU system is more efficient than previous methods in many ways.…”

“…Third, the SWPU system can join two metanephroi at one time, whereas connecting the recipient ureter to two metanephroi ureters is difficult. Because previous studies showed that the total mass of the developed metanephros correlated with the duration of anephric rat survival (13), the SWPU system is thought to be more effective than conventional uretero-ureterostomies in improving survival time. Fourth, connecting the recipient ureter with a bladder grown from a cloacal transplant is easier than uretero-ureterostomy because the recipient ureter is very large compared with the metanephroi ureters, and the urine-expanded cloacal-grown bladder is either larger than or similar in size to the recipient ureter.…”

Functional Human Podocytes Generated in Organoids from Amniotic Fluid Stem Cells

“…Similar approaches in recipients with different diseases have shown that embryonic kidneys can initiate regenerative processes in damaged kidney tissue, 24 regulate arterial blood pressure, 25 exhibit metabolic properties 26 and prolong life in anephric rats. 27,28 Although these methods showed promising therapeutic potential, they cannot be applied in experiments that seek to grow chimeric organs in vivo for testing the ability of stem cells to contribute to different structures in the organ and modeling human development or disease. In particular, the compact nature of the tissue makes the introduction of exogenous cells into the system difficult and their widespread dispersal to make fine-grained chimeras impossible.…”

The Lymph Node as a New Site for Kidney Organogenesis

“…Hammerman's group first suggested that whole rat metanephroi implanted into the omentum might enlarge, become vascularized, and form mature tubules and glomeruli [9]. However, other studies showed that transplanted metanephroi can grow and develop for only a short time in the host omentum [10], unless an end-to-end anastomosis to the host ureters is performed [11]. Only a few reports have shown that it is technically feasible to microsurgically connect donor and host ureters.…”

“…Only a few reports have shown that it is technically feasible to microsurgically connect donor and host ureters. In these studies, ureteroureterostomy slowed the progression of kidney failure in nephrectomized animals [12], prolonged short-term survival of anephric rats [11], or caused a rise in blood pressure in acutely hypotensive rats [13]. Although promising, these results point to several limitations in the clinic that also include postoperative adhesions and intestinal obstruction following omental manipulation [14,15].…”