After Intestinal Transplantation Kidney Function Is Impaired by Downregulation of Epithelial Ion Transporters in the Ileum.
BACKGROUND
Intestinal transplantation is a treatment option for intestinal failure. Although nephrotoxic medication after transplantation is a major cause for posttransplant renal insufficiency, it remains unclear why kidney dysfunction is particularly frequent after intestinal transplantation.


METHODS
This study analyzed messenger RNA expression of NHE3, DRA, and CFTR in 404 biopsies obtained between day 2 and 1508 from the terminal ileum of 10 adult intestinal transplant recipients.


RESULTS
The time courses of immunosuppression and glomerular filtration rate were correlated. In the first posttransplant year, expression of NHE3 and DRA, which mediate NaCl absorption, was diminished to a greater degree than that of CFTR, which mediates chloride secretion. Reduced NHE3 and DRA expression was associated with high tacrolimus trough levels. Titration of tacrolimus to low levels by year 2 was paralleled by partially restored NHE3 and DRA expression. In cell culture experiments, similar effects of tacrolimus on transporter expression were detected. In patients, both reduced tacrolimus levels and recovery of NHE3 and DRA expression were associated with stabilization of renal function.


CONCLUSIONS
Our data strongly suggest that tacrolimus impairs absorption of NaCl and water from the transplanted ileum, leading to volume depletion and impaired renal function. This may be reversible by reduction of tacrolimus to lower levels without increased rates of rejection or chronic graft failure.
First Medical Department, University of Tübingen, Tübingen, Germany; Division of Gastroenterology and Endocrinology, University Medical Center Rostock, Rostock, Germany.
J
J
Reiner
First Medical Department, University of Tübingen, Tübingen, Germany.
C-J
CJ
Hsieh
Division of Gastroenterology and Endocrinology, University Medical Center Rostock, Rostock, Germany.
C
C
Straarup
Division of Gastroenterology and Endocrinology, University Medical Center Rostock, Rostock, Germany.
P
P
Bodammer
Division of Gastroenterology and Endocrinology, University Medical Center Rostock, Rostock, Germany.
H
H
Schäffler
First Medical Department, University of Tübingen, Tübingen, Germany.
F
F
Graepler
Department of General, Visceral and Transplantation Surgery, University of Tübingen, Tübingen, Germany.
D
D
Stüker
Department of General, Visceral and Transplantation Surgery, University of Tübingen, Tübingen, Germany.
T
T
Kratt
Department of General, Thoracic, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock, Germany.
M
M
Linnebacher
Department of General, Visceral and Transplantation Surgery, University of Tübingen, Tübingen, Germany.
S
S
Nadalin
Department of General, Visceral and Transplantation Surgery, University of Tübingen, Tübingen, Germany; Department of General, Thoracic, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock, Germany.
M
M
Witte
Department of General, Visceral and Transplantation Surgery, University of Tübingen, Tübingen, Germany.
A
A
Königsrainer
First Medical Department, University of Tübingen, Tübingen, Germany; Division of Gastroenterology and Endocrinology, University Medical Center Rostock, Rostock, Germany. Electronic address: georg.lamprecht@med.uni-rostock.de.
G
G
Lamprecht
D000328:Adult; D000368:Aged; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005767:Gastrointestinal Diseases / Q000378:metabolism / Q000601:surgery*; D005919:Glomerular Filtration Rate; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007422:Intestines / Q000637:transplantation*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D000076988:Sulfate Transporters; D016559:Tacrolimus / Q000627:therapeutic use
C505032:CFTR protein, human; D027963:Chloride-Bicarbonate Antiporters; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C081011:SLC26A3 protein, human; C000613385:SLC9A3 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016559:Tacrolimus