The use of dd-cfDNA as a predictive tool for future proteinuria
Stanley Jordan1, Puneet Sood2, Jonathan S. Bromberg3, Dan Brennan4.
1Cedars-Sinai, Los Angeles, CA, United States; 2University of Pittsburgh Medical Center, Pittsburgh, PA, United States; 3University of Maryland, Baltimore, MD, United States; 4The Johns Hopkins Hospital, Baltimore, MD, United States
Background: Most allografts with proteinuria >1500 mg/dL have new glomerular pathology. In contrast, lower levels of proteinuria are generally associated with non-glomerular, nonspecific histologic changes. The relationship between proteinuria and graft survival is independent of other variables1, allowing stratification of risk in patients with or without glomerular pathology. Donor-derived cell-free DNA (dd-cfDNA) is also known to allow risk stratification of patients, quantifying molecular injury. As proteinuria is routinely monitored periodically post-transplant, once present it suggests the damage has already occurred. Assessing whether elevation in dd-cfDNA is predictive of new proteinuria may help to predict long term outcome.
Methods: 99 patients identified from the DART study had dd-cfDNA (AlloSure®) and proteinuria measured 1-10 times during the first-year post transplant and 1-6 times during follow up visits during the second year. Clinically significant proteinuria was defined as patients with grade ‘++’ proteinuria or higher sustained over 3 visits. The fraction of patients with positive proteinuria from year two was compared to the fraction from year one (day 14-365) in patients with ≥1 elevated dd-cfDNA (AlloSure ≥1%) in the first year vs. those without dd-cfDNA elevation. Association between elevated dd-cfDNA (≥1%) in year 1 and de novo positive proteinuria in year 2 was also tested.
Results: 20 patients with ≥ 1 elevated dd-cfDNA in days 14 - 365 were compared to 79 patients without dd-cfDNA elevation. Proteinuria was more common in the second year in patients with elevated dd-cfDNA in the first year (4/20 = 20%) than in those without (0/79 = 0%, P = 0.001, Fisher’s exact test). Of the 82 patients who did not have positive proteinuria in the first year, patients with elevated dd-cfDNA in year 1 were more likely to develop de novo proteinuria in year 2, (8%) than those without elevated dd-cfDNA, (0%), however due to the small sample size this was not statistically significant (p=0.146, Fisher’s exact test).
Conclusion: The cause of new or worsening proteinuria remains multifactorial; however, elevations in 1st year AlloSure® dd-cfDNA (≥1%) are associated with significant increase in proteinuria in year 2. dd-cfDNA as a marker of injury may have utility beyond detecting acute events, where regular surveillance may be a useful tool in prediction of long-term outcomes, especially when combined with other measures of immune injury to allografts.
 Amer H, Cosio FG. Significance and management of proteinuria in kidney transplant recipients. J Am Soc Nephrol 2009; 20(12):2490-2
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