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Composition and method for improving function of embryonic kidney transplants

a kidney transplant and composition technology, applied in the field of composition and method for improving the function of embryonic kidney transplants, can solve the problems of renal allotransplantation, unsatisfactory xenografting of kidneys, and further loss of renal function

Inactive Publication Date: 2006-06-22
WASHINGTON UNIV IN SAINT LOUIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes methods and compositions for improving the function of kidneys that are transplantated into a recipient. This is achieved by using isolated embryonic metanephric tissue in combination with a growth factor containing composition that includes various growth factors such as insulin-like growth factors, vascular endothelial growth factor, transforming growth factors, and others. The growth factors can be added to the tissue before or after transplantation. The invention also includes the use of growth factor compositions in the preparation of a medicament for the growth and development of embryonic metanephric tissue prior to implantation. The technical effect of the invention is to enhance the development and function of kidneys that are transplantated into a recipient.

Problems solved by technology

However, these compensatory changes are often transient and under some circumstances maladaptive in that they may lead to further loss of renal function.
Another treatment is renal allotransplantation, which is limited by the number of available organs for transplantation.
However, the results of xenografting of kidneys has been unsatisfactory, and this technique has remained an experimental one for three decades.
However, connection of donor nephrons to the collecting system of hosts, that would be required for plasma clearance to occur, could not be demonstrated.
It was concluded that the neonatal kidney, which has a rim of undifferentiated cortex (the nephrogenic zone) can facilitate the differentiation of an embryonic implant, but that this ability is lacking in the fully-differentiated adult kidney.
They suggested that the presence of cysts in developed donor metanephroi, coupled with their inability to demonstrate any connection between the donor and host collecting systems, raised the possibility that transplanted metanephroi become obstructed in the subcapsular site.

Method used

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  • Composition and method for improving function of embryonic kidney transplants

Examples

Experimental program
Comparison scheme
Effect test

example 1

Allogeneic Transplantation of Metanephroi into Host Kidney

Transplantation Methods

[0057] Whole metanephroi, with renal capsules intact, were removed surgically under a dissecting scope from E15 Sprague-Dawley rat embryos (Harlan, Indianapolis Ind.), and suspended in saline solution on ice under sterile conditions. Within 45 minutes after removal, four metanephroi per recipient were implanted under the capsule of normal kidneys of 6 week old outbred normal (NL) female Sprague-Dawley rats. Some of the recipient rats had undergone contralateral nephrectomy (UNX) or unilateral nephrectomy and one-half contralateral kidney infarction (1½ NX) using previously described procedures (Rogers et al., supra; Rogers et al., (1998) Kidney Int. 54:27-37). Transplanted metanephroi were approximately 700 um in diameter and, as would be expected for this stage of development, contained segments of ureteric bud and some developing nephron precursors, but no glomeruli. When noted, recipient rats rece...

example 2

Xenogeneic Transplantation of Metanephroi into Host Kidney

[0064] Metanephroi from N.I.H. Swiss mouse metanephroi (E14) were transplanted underneath the renal capsule of 1½ NX Sprague Dawley rats. Following implantation, host rats were treated with cyclosporine A (CSA) (5 mg / kg body weight injected subcutaneously once per day), or vehicle (peanut oil). Four weeks post-transplantation, all that remained of the metanephroi implanted into the kidneys of rats that did not receive CSA treatment was a mass of fibrotic tissue. However, in CSA-treated recipients metanephroi grew, vascularized and developed. The presence of a urothelial-lined cavity containing a renal papilla in the transplanted metanephroi indicated that glomerular filtration occurs in the donor renal tissue.

example 3

Allogeneic Transplantation of Metanephroi into Host Omentum

[0065] Metanephroi were dissected from E15 sprague-Dawley rats as previously described in Example 1 and implanted into 6 week old outbred UNX Sprague Dawley rats and into rats that had no native renal tissue removed, in omental folds near the recipients' kidneys. Recipient rats received no immunosuppression post-transplantation.

[0066] After 6 weeks, transplanted metanephroi were removed and examined. They had assumed a kidney-like shape in situ, had intact ureters and were approximately one-third the diameter of native kidneys. Sections of transplanted metanephroi were prepared and stained with hematoxylin and eosin. Both cortical and medullary tissue were present. Cortices contained well-developed glomeruli containing red blood cells, proximal tubules with well-developed brush border membranes, and distal tubules. Medullas contained well-developed collecting ducts. Ureters were lined with transitional epithelium. Rare acc...

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Abstract

Methods and compositions are disclosed for use with embryonic metanephric tissue so as to increase the functioning renal mass obtained upon transplantation into a recipient.

Description

RELATED APPLICATIONS [0001] This application claims continuing status to U.S. application Ser. No. 09 / 472,662, filed Dec. 27, 1999; which is a continuation-in-part of 09 / 222,460, filed Dec. 29, 1998, incorporated herein by reference.[0002] This invention was made with Government support from the National Institute of Health Grant / Contract No. P50 DK45181. The U.S. Government may have certain rights to this invention.BACKGROUND OF THE INVENTION [0003] The metanephric kidneys originate during the fifth week of gestation in humans, during day 12 of embryonic rat development, and during day 20-28 of embryonic pig development, when outgrowths of the mesonephric ducts, so-called ureteric buds, collect about their distal ends, intermediate mesoderm (metanephric blastema) located caudal to the mesonephros. The outgrowths push radially into the surrounding mass of metanephric blastema and give rise to the collecting ducts of the kidneys. The proximal ends of the ureteric bud give rise to the...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/12C12N5/07A01N63/00A61K31/07A61K35/22A61K35/23A61K38/00A61K38/18A61K38/27A61P13/12C12N5/073C12N5/077
CPCA61K35/22A61K38/18A61K2300/00A61P13/12
Inventor HAMMERMAN, MARC R.ROGERS, SHARON A.
Owner WASHINGTON UNIV IN SAINT LOUIS
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