Differentiation between chronic rejection and chronic cyclosporine toxicity by analysis of renal cortical mRNA
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Published on: November 8, 2015
Klaas Koop1, Rene C Bakker, Michael Eikmans
1Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. k.koop@lumc.nl
Background:
In kidney transplantation, chronic allograft nephropathy (CAN) is the major cause of graft loss. Causes of CAN include chronic rejection and chronic cyclosporine A (CsA) nephrotoxicity. It is necessary to differentiate between these two entities in order to apply the appropriate therapeutic regimen for the individual patient, but this is hampered by the lack of discriminating functional and morphologic parameters. We investigated whether renal cortical mRNA levels for several matrix proteins can serve as discriminating parameters.
Methods:
Patients with chronic rejection (N= 19) and chronic CsA toxicity (N= 17) were selected by clinical and histologic criteria. Protocol biopsies without histologic abnormalities, taken at 6 months after transplantation from patients receiving CsA, were used as controls (N= 6). Total RNA was extracted from the renal biopsy tissue, and mRNA levels of transforming growth factor-beta (TGF-beta) and the extracellular matrix (ECM) molecules collagen Ialpha1, IIIalpha1, IValpha3, decorin, fibronectin, and laminin beta2 were measured by real-time polymerase chain reaction (PCR).
Results:
In both patient groups, the mean collagen IValpha3 and fibronectin mRNA levels were significantly elevated compared to those in controls, whereas only in CsA toxicity were the laminin beta2 and TGF-beta mRNA levels significantly increased. The increase of laminin beta2 and TGF-beta mRNA levels was significantly higher in the CsA toxicity group than in the chronic rejection group (P < 0.001 and P= 0.004, respectively). Receiver-operating characteristic (ROC) curve analysis showed that with a 15.6-fold increase in laminin beta2 mRNA expression as cut-off point, the presence of CsA toxicity could be predicted with an 87% sensitivity and an 88% specificity.
Conclusion:
Renal laminin beta2 and TGF-beta mRNA levels can be used to differentiate between chronic rejection and chronic CsA toxicity in renal transplants. The method of mRNA quantification might be applicable as an additional diagnostic tool in clinical practice.
Insights
Differentiating chronic rejection from cyclosporine A (CsA) toxicity in kidney transplants is crucial. Renal laminin beta2 and TGF-beta mRNA levels can distinguish between these conditions, aiding in diagnosis.
Area of Science:
- Nephrology
- Transplantation Immunology
- Molecular Diagnostics
Background:
- Chronic allograft nephropathy (CAN) is the primary cause of kidney graft loss.
- CAN results from chronic rejection or chronic cyclosporine A (CsA) nephrotoxicity.
- Distinguishing between these causes is vital for appropriate patient treatment but lacks reliable parameters.
Purpose of the Study:
- To investigate if renal cortical mRNA levels of matrix proteins can differentiate chronic rejection from CsA toxicity.
- To identify specific mRNA markers for distinguishing between these two causes of CAN.
Main Methods:
- Real-time PCR was used to measure mRNA levels of TGF-beta and ECM molecules (collagen Ialpha1, IIIalpha1, IValpha3, decorin, fibronectin, laminin beta2).
- Analysis was performed on renal biopsy tissue from kidney transplant patients with chronic rejection (N=19), CsA toxicity (N=17), and healthy controls (N=6).
Main Results:
- Collagen IValpha3 and fibronectin mRNA levels were elevated in both patient groups compared to controls.
- Laminin beta2 and TGF-beta mRNA levels were significantly increased in CsA toxicity patients.
- Higher laminin beta2 and TGF-beta mRNA levels in CsA toxicity predicted CsA toxicity with 87% sensitivity and 88% specificity.
Conclusions:
- Renal laminin beta2 and TGF-beta mRNA levels effectively differentiate chronic rejection from CsA toxicity in kidney transplants.
- mRNA quantification shows potential as an additional diagnostic tool in clinical practice for transplant patients.