Kidney Transplantation Clinical Trial
Official title:
Study of Renal Transporters and Their Regulators After Renal Transplantation
Previous studies in animals revealed, that the activity of certain transporters along the nephron is changed with acute rejection after renal transplantation. We intend to investigate underlying mechanisms occurring in man in renal biopsy specimens obtained from patients because of acute rejection of the transplant or chronic transplant nephropathy.
After renal transplantation, caused by ischemia or rejection, often renal transport
processes are disturbed. These dysfunctions which are similar to the Fanconi syndrome as
well as renal tubular acidosis occur in the early phase after transplantation. Irreversible
injuries develop caused by nephrotoxicity of immunosuppressants and renal transplant artery
stenoses. Although this has impact on clinical follow up and prognosis of the transplant, up
to now, it still has to be clarified by which mechanisms the tubular transport processes are
impaired.
In an animal model, we demonstrated first, that expression of membrane proteins is
specifically modulated early after transplantation, indicating that changes in expression
and function in these models are not due to general necrosis or apoptosis. Second, our
results differ from data obtained after ischemia / reperfusion. Third, the regulatory
pattern seems not to be the consequence of a systemic effect. We suppose that changes in
expression of transporters and receptors after transplantation and rejection are
continuously modulated, which may influence the prognosis of the graft. The data suggest
that transplantation with acute rejection leads to ischemia-independent changes in the
regulation of transporters along the nephron (Velic A, Gabriëls G, Hirsch JR, Schröter R,
Edemir B, Paasche S, Schlatter E. Acute rejection after rat renal transplantation leads to
downregulation of Na+ and water channels in the collecting duct. Am J Transplant. 2005, 5:
1276-85. Velic A, Hirsch JR, Bartel J, Thomas R, Schröter R, Stegemann H, Edemir B, August
C, Schlatter E, Gabriëls G: Renal transplantation modulates expression and function of
receptors and transporters of rat proximal tubules. J Am Soc Nephrol. 2004, 15: 967-77).
By means of microarray analysis we examined the expression of genes after renal
transplantation in rats. Of the about 18.000 genes, in the model of acute rejection more
than 55% of the genes were changed in their expression compared to controls, while
transplantation without rejection only induced a change in expression of 30% of the genes.
With rejection, about 50% of these genes were upregulated and about 50 % downregulated.
The regulated genes were classified in different groups. An essential part of the genes
upregulated with rejection, as expected, point to a massive immune response. With rejection,
a large amount of the genes coding for proteins with transport activity or proteins involved
in metabolism are downregulated (e.g. amino acid transport, glucose transport, K+-, Ca++-
and phosphate transport, transport of water, pH regulation). It was shown that, with
rejection, signal transduction pathways involved in protein catabolism and immune response
are upregulated.
By the present study in renal biopsies of about 200 transplanted individuals with acute
rejection or chronic transplant nephropathy, we intend to examine the regulation of
transport systems and regulatory factors during a period of two years. Our hypothesis is
that the activity of transporters along the nephron is changed with renal transplantation,
acute rejection reaction, or chronic transplant nephropathy. We intend to investigate
underlying mechanisms in renal biopsy specimens obtained from patients because of acute
rejection reaction or chronic transplant nephropathy.
The study has been designed to analyze whether the renal transport system factors we found
to be differentially regulated in rats are regulated similarly with transplant rejection or
transplant nephropathy in man.
The findings obtained by these studies also are indispensable regarding a plain
comprehension of the development of tubule dysfunction after renal transplantation in man.
The examination of the material serves to explore basic pathophysiological mechanisms with
rejection and transplant nephropathy.
Details
Individuals with a renal transplant in whom a renal biopsy is indicated because of clinical
reasons will be informed about aims and course of the study as well as potential risks and
complications of the biopsy procedure. Then they will be asked to participate.
Should the patient decide for participation, he again will be made aware about potential
risks and complications of the biopsy procedure using the official information sheet of the
hospital on biopsy procedures and a special information sheet affiliated to the study
documents. After reading the information sheets, the patients will be asked to sign the
agreement. With the patients´ approval, two specimens of the renal transplant will be
obtained. The Patient will be monitored for 24 hours clinically and by blood pressure
measurements, urinalysis as well as by ultrasound scanning.
If there are no complaints and the controls are alright, the patient may check out of the
hospital but is asked to return for a control examination one week later. At this
presentation a physician familiar with the study will examine the patient clinically and by
ultrasound. The levels of electrolytes, BUN and serum-creatinine will be detected and a
venous blood gas analysis will be performed. In case that regarding the consequences of the
biopsy everything is fine, the study is finished for this patient. He will be asked to
present again, if new symptoms will arise.
While one part of the specimens obtained for diagnostics will be prepared for the study of
gene expression immediately after the biopsy procedure, the other will be transported to the
institute of pathology and worked up as usual.
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