Kidneys donated by people born with a small variation in the code of a key gene may be more likely, once in the transplant recipient, to accumulate scar tissue that contributes to kidney failure, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai and published in the Journal of Clinical Investigation.  

If further studies prove the variation to cause fibrosis in the kidneys of transplant recipients, researchers may be able to use it to better screen potential donors and improve transplant outcomes. Furthermore, uncovering the protein pathways that trigger kidney fibrosis may help researchers design drugs that prevent this disease process in kidney transplant recipients, and perhaps in all patients with chronic kidney disease.

"It is critically important that we identify new therapeutic targets to prevent scarring within transplanted kidneys, and our study has linked a genetic marker, and related protein pathways, to poor outcomes in kidney transplantation," said Barbara Murphy, MD, Chair, Department of Medicine, Murray M. Rosenberg Professor of Medicine (Nephrology) and Dean for Clinical Integration and Population Health at the Icahn School of Medicine at Mount Sinai. "Drug designers may soon be able to target these mechanisms."

Even the smallest genetic variations, called single nucleotide polymorphisms (SNPs), can have a major impact on a trait by swapping just one of 3.2 billion "letters" making up the human DNA code. The current study found a statistically significant association between SNP identified as rs17319721 in the gene SHROOM3 and progressive kidney fibrosis and function loss in a group of kidney donors, mostly of European descent. In many cases, certain SNPs will be more common in families or ethnic groups.

More about SHROOM3
The study found that when SHROOM3 is present in the kidney donor, correlates with a greater quantity of SHROOM3 protein in the organ once transplanted. More SHROOM3 turns on more transcription factor 7-like 2 (TCF7L2). This, in turn, turns on several genes with many functions in cells. TCF7L2 is a member of the Wnt signaling pathway, and ultimately results in increased signaling by transforming growth factor beta 1 (TGF-β1) and increased COL1A1 expression.

TGF-β1 signals for the building of connective tissue, which normally restores tissue architecture as part of healing, but may also drive fibrosis in the wrong context. COL1A1 (Collagen, type I, alpha 1) is the gene that codes for the major component in type I collagen, the major protein component of connective tissues (e.g. bone. cartilage) and of scar tissue that forms as wounds heal. Together, these factors contribute to excess tissue fibrosis.

While SHROOM3 had been associated with chronic kidney disease by earlier studies, its specific role in transplant injury and kidney fibrosis was unknown going into this study.

The current study results proceed from an ongoing NIH-sponsored study in kidney transplant recipients [Genomics of Chronic Allograft Rejection (GOCAR) study]. The research team performed biopsies of transplanted kidneys at pre-specified time points after transplantation and matched gene activation (expression) levels in the transplanted kidneys 3 months after transplantation to indices of transplant dysfunction at 12 months.

The link between the SHROOM3 gene, related protein pathways and fibrosis detected in the GWAS was confirmed in studies of mice engineered to be models of human kidney disease.

"Further work is needed before a clinical application of the study can be introduced," said Murphy. "However, our results are a crucial and optimistic step towards improving treatment of chronic kidney disease."