Utility of Serial Donor-derived Cell-free DNA Measurements for Detecting Allograft Rejection in a Kidney Transplant Recipient After PD-1 Checkpoint Inhibitor Administration.

BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) is a useful biomarker of rejection that originates from allograft cells undergoing injury. Plasma levels <1% in kidney transplant recipients have a high negative predictive value for active allograft rejection. The utility of this biomarker in kidney transplant recipients receiving immune checkpoint inhibitor therapy is unknown. METHODS: We describe a case in which serial dd-cfDNA monitoring facilitated the use of immune checkpoint inhibitor therapy, which is known to be associated with high rates of rejection, in a kidney transplant recipient with metastatic cancer. RESULTS: A 72-y-old man with end-stage kidney disease secondary to autosomal dominant polycystic kidney disease underwent living unrelated kidney transplant in December 2010. His immunosuppression regimen included tacrolimus, mycophenolate, and prednisone. In July 2017, he presented with metastatic cutaneous squamous cell carcinoma. After his disease progressed through radiation therapy and cetuximab, he received pembrolizumab (antiprogrammed cell death protein 1). His dd-cfDNA level was undetectable at baseline, then increased during treatment but remained <1%. This trend, despite fluctuations in serum creatinine levels during therapy, allowed for continuation of pembrolizumab and successful treatment of his metastatic cancer without clinically evident allograft rejection. After discontinuation of pembrolizumab, dd-cfDNA levels fell below the level of detection. Genetic analysis of the cutaneous squamous cell carcinoma demonstrated a genetic profile distinct from the dd-cfDNA, indicating that tumor lysis did not impact increases in dd-cfDNA. CONCLUSIONS: Serial dd-cfDNA measurements may provide a useful, noninvasive biomarker for detecting allograft injury that may facilitate the use of immunomodulatory therapies in organ transplant recipients with cancer.

Angiotensin II receptor 1 antibodies associate with post-transplant focal segmental glomerulosclerosis and proteinuria.

BACKGROUND: Angiotensin II type 1 receptors (AT1Rs) are expressed on podocytes, endothelial and other cells, and play an essential role in the maintenance of podocyte function and vascular homeostasis. The presence of AT1R antibodies (AT1R-Abs) leads to activation of these receptors resulting in podocyte injury and endothelial cell dysfunction. We assessed the correlation between AT1R-Abs and the risk of post-transplant FSGS. METHODS: This is a retrospective study, which included all kidney transplant recipients with positive AT1R-Abs (≥ 9 units/ml), who were transplanted and followed at our center between 2006 and 2016. We assessed the development of biopsy proven FSGS and proteinuria by urine protein to creatinine ratio of ≥1 g/g and reviewed short and long term outcomes. RESULTS: We identified 100 patients with positive AT1R-Abs at the time of kidney transplant biopsy or proteinuria. 49% recipients (FSGS group) had biopsy-proven FSGS and/or proteinuria and 51% did not (non-FSGS group). Pre-transplant hypertension was present in 89% of the FSGS group compared to 72% in the non-FSGS group, p = 0.027. Of the FSGS group, 43% were on angiotensin converting enzyme inhibitors or angiotensin receptor blockers prior to transplantation, compared to 25.5% in the non-FSGS group, p = 0.06. Primary idiopathic FSGS was the cause of ESRD in 20% of the FSGS group, compared to 6% in the non-FSGS group, p = 0.03. The allograft loss was significantly higher in the FSGS group 63% compared to 39% in non-FSGS. Odds ratio and 95% confidence interval were 2.66 (1.18-5.99), p = 0.017. CONCLUSIONS: Our data suggest a potential association between AT1R-Abs and post-transplant FSGS leading to worse allograft outcome. Therefore, AT1R-Abs may be considered biomarkers for post-transplant FSGS.

High-Output Cardiac Failure and Coronary Steal With an Arteriovenous Fistula.

Creation of an arteriovenous access for hemodialysis can provoke a sequence of events that significantly affects cardiovascular hemodynamics. We present a 78-year-old man with end-stage renal disease and concomitant coronary artery disease previously requiring coronary artery bypass grafting including a left internal mammary graft to the left anterior descending artery, ischemic cardiomyopathy with left ventricular systolic dysfunction, and severe aortic stenosis who developed hypotension unresponsive to medical therapy after recent angioplasty of his ipsilateral arteriovenous fistula for high-grade outflow stenosis. This case highlights the long-term effects of dialysis access on the cardiovascular system, with special emphasis on complications such as high-output cardiac failure and coronary artery steal syndrome. Banding of the arteriovenous fistula provided symptomatic relief with a decrease in cardiac output. Avoidance of arteriovenous access creation on the ipsilateral upper extremity in patients with a left internal mammary artery bypass graft may prevent coronary artery steal syndrome.