From MedScape.com, American Journal of Transplantation
Screening of Living Kidney Donors for Genetic Diseases Using a Comprehensive Genetic Testing Strategy
Abstract
Related living kidney donors (LKDs) are at higher risk of end-stage renal disease (ESRD) compared with unrelated LKDs. A genetic panel was developed to screen 115 genes associated with renal diseases. We used this panel to screen six negative controls, four transplant candidates with presumed genetic renal disease and six related LKDs. After removing common variants, pathogenicity was predicted using six algorithms to score genetic variants based on conservation and function. All variants were evaluated in the context of patient phenotype and clinical data. We identified causal variants in three of the four transplant candidates. Two patients with a family history of autosomal dominant polycystic kidney disease segregated variants in PKD1. These findings excluded genetic risk in three of four relatives accepted as potential LKDs. A third patient with an atypical history for Alport syndrome had a splice site mutation in COL4A5. This pathogenic variant was excluded in a sibling accepted as an LKD. In another patient with a strong family history of ESRD, a negative genetic screen combined with negative comparative genomic hybridization in the recipient facilitated counseling of the related donor. This genetic renal disease panel will allow rapid, efficient and cost-effective evaluation of related LKDs.
Introduction
Kidney transplantation is superior to long-term dialysis for the management of end-stage renal disease (ESRD) because it provides greater long-term survival and better quality of life. Nevertheless, there is an ever-increasing gap between the need for transplantation and the availability of donor kidneys, with >120 000 patients currently on the deceased donor waitlist in the United States alone. This has resulted in an increasing push to encourage living donation, and today there are almost as many living donors as deceased donors annually in the United States.[1] Living kidney donor (LKD) transplants, for those fortunate to receive one, bypass the long waiting time, reduce the likelihood of death while waiting and provide better long-term allograft and recipient survival compared with deceased donor kidneys.[2,3] In some parts of the world, LKDs are the principal or only source of transplanted organs, and where long-term dialysis is prohibitively expensive or unavailable, LKD transplants provide the only available therapy for ESRD.
Living donor nephrectomy is generally considered acceptable medical practice, even though there are real risks for the donor, including death, serious injury and failure of the remaining kidney. Recent retrospective studies examining long-term outcomes of living donation compared with matched nondonor cohorts reported an increased 15-year and lifetime risk of ESRD for LKDs.[4,5] Although the absolute risk is arguably small, the relative risk is 30 per 10 000 over 15 years and 90 per 10 000 over a lifetime compared with four per 10 000 and 14 per 10 000 in matched controls. Within subpopulations, black men have a 15-year risk of 90 per 10 000 compared with just nine per 10 000 for white women.[4]Although not statistically significant, there is a twofold increased risk of ESRD among biologically related LKDs compared with unrelated LKDs.[4] The increased risk may reflect shared inheritance of genetic variants that are deleterious or a common environmental exposure that increases susceptibility to kidney disease.
In the United States, 40% of all LKDs are biologically related to their recipients.[1] Many are siblings or adult children of patients with ESRD and are in their third and fourth decades of life, making it difficult to predict future risk of kidney disease. In addition, to guide focused genetic testing of related family members for a specific inherited disease, the transplant recipient's cause of ESRD must be known. Together, diabetes and hypertension are the two most important reported causes of ESRD and account for 60% of the waitlist.[1,6] Most patients with diabetes and/or hypertension and chronic kidney disease (CKD) do not receive a kidney biopsy to verify the diagnosis, and recent studies estimated that as many as 35% of patients with presumed diabetic or hypertensive nephropathy may actually have an alternative diagnosis.[7–9]
Traditionally, establishing and/or confirming the diagnosis of a presumed genetic disease has required Sanger sequencing of the suspected gene for pathogenic variants.[10] When candidate genes are large, like COL4A5, sequencing is costly and time consuming. When the disease is heterogeneous, like focal segmental glomerulosclerosis (FSGS), serial gene-by-gene screening approaches are inefficient and impractical. These constraints can be largely overcome by using high-throughput approaches to DNA sequencing (i.e. next-generation sequencing [NGS] or massively parallel sequencing [MPS]) to sequence a large number of genes simultaneously. Targeted NGS panels have been developed to evaluate patients with a single phenotype, such as steroid-resistant nephrotic syndrome, FSGS and some ciliopathies.[11–14]
We developed a targeted renal panel that includes 115 genes implicated in a variety of kidney diseases to facilitate a diagnosis in patients with suspected genetic renal disease. We validated this panel for the evaluation of selected LKDs in whom the related transplant recipient's phenotype raised suspicion of or clearly indicated an inherited renal disease. We reported our findings from a pilot study of six controls, four transplant candidates and their six related donors. [Read more]
PKD Research
From Nature.com
Gift of Life
Misty Cass (left) has no doubts about donating a kidney to save the life of her boyfriend, Kerrville Police Department Investigator Darin Trahan (right). Both of Trahan’s kidneys are failing due to Polycystic Kidney Disease.
The remarkable chain of events and community support have been overwhelming to a local police officer, who will be receiving a new kidney and a new chance at life and in the process save the lives of many others.
Kerrville Police Department Investigator Darin Trahan thought he had some sort of infection when he made a doctor’s appointment in 2005.
He expected to receive the usual prescription for antibiotics and then he would go on with his life. Instead, Trahan discovered his illness could someday take his life.
“I thought I had a kidney infection or something,” Trahan said. “But they came back and said I had Polycystic Kidney Disease.”
Trahan said he was told there was no cure for the disease and that he would eventually need a kidney transplant, as the disease is affecting both of his kidneys.
“They said to go on with my life and try to eat healthy and be active,” Trahan said. “They said, eventually my kidneys would begin to fail and then we would look at getting on a kidney transplant list.”
Trahan said doctors told him that his kidneys would have to be functioning at less than 20 percent capacity before being accepted on the national organ donor list.
So Trahan went about his daily routine, never missed a day of work, and quietly dealt with the reality of his illness.
“I didn’t really tell anyone,” Trahan said. “I didn’t even tell my children. I felt there was no reason to worry anyone at that time. I decided to wait and tell them when it was absolutely necessary.”
It became necessary nearly 11 years later, when Trahan’s kidney function began to drastically decrease.
“My kidney function is now at 17 percent,” Trahan said.
Trahan began the process of being accepted into the organ donation program. He made an appointment at the Methodist Specialty and Transplant Hospital to begin testing, so that a match could be identified. He was accompanied by his girlfriend of nearly two years, Misty Cass.
Cass chose to also be tested to see if she was a match, however, she was not.
The remarkable chain of events that were alluded to earlier begin here.
While Cass was not a blood match for Trahan, she was told she could become an “Altruistic Donor,” which means that she and Trahan would be paired in a donor pool. Cass’ kidney would go to someone who was paired with an altruistic donor that matched Trahan.
“The process is very complicated,” Trahan said. “In total, there will be 16 people involved, providing kidney transplants for eight people.”
Trahan said the surgeries will take two days to complete and will begin this week on Wednesday, March 8.
“Misty and I will go for our pre-op on Monday and Tuesday,” Trahan said.
When speaking of Cass’ willingness to donate a kidney on his behalf, Trahan gets a little emotional.
“She’s my hero,” Trahan said. “I’ve told her she didn’t have to do it. I’ve tried to talk her out of it.”
Cass said she did not hesitate when presented with the opportunity.
“He is a good man. He has served his community well and I love him,” Cass said. “This (surgery) will save his life. To be honest, I would do it for anyone I care about.”
Cass is not the only person who stepped up to help Trahan. In fact, the community support for Trahan, a public servant, has been phenomenal.
“After I told my family about my disease, my brother posted something on Facebook, asking for prayers,” Trahan said. “Just from that post, I have received offers from at least 40-50 people, who said they would be willing to get to tested to donate as well. I told them ‘thank you,’ and explained how much I appreciated their offer, but I have a donor.”
One donor, however, would not relent.
Trahan said Caitlin Eubank, the wife of a former KPD officer, was insistent that she help. Knowing that she was not a blood-match, but could assist in being an altruistic donor fueled Eubank’s cause. [Read more]
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