Graft‐derived cell‐free DNA (donor‐derived cell‐free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell‐free DNA that is graft‐derived. The present study evaluated the diagnostic validity of absolute measurements of graft‐derived cell‐free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft‐derived cell‐free DNA, total cell‐free DNA and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. 61 samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver‐operator characteristic area under the curves of graft‐derived cell‐free DNA and graft fraction were 0.91 (95% CI 0.82‐0.98) and 0.89 (95% CI 0.79‐0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft‐derived cell‐free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.

Export Kidney transplant recipients undergo lifelong monitoring of allograft function and evaluation for transplant complications. The current monitoring paradigm utilizes blood, urine, and tissue markers that are insensitive, nonspecific, or invasive to obtain. As a result, problems are detected late, after significant damage has accrued, and often beyond the time at which complete resolution is possible. Indeed, most kidney transplants eventually fail, usually because of chronic rejection and other undetected injury. There is a clear need for a transplant-specific biomarker that enables a proactive approach to monitoring via early detection of reversible pathology. A biomarker that supports timely and personalized treatment would assist in achieving the ultimate goal of improving allograft survival and limiting therapeutic toxicity to the recipient. Donor-derived cell-free DNA (ddcfDNA) has been proposed as one such transplant biomarker. Although the test is presently utilized most in the United States, it is conceivable that its use will become more widespread. This review covers aspects of ddcfDNA that support informed use of the test by general nephrologists, including the basic biology of ddcfDNA, methodological nuances of testing, and general recommendations for use in the kidney transplant population. Clinical contexts are used to illustrate evidence-supported interpretation of ddcfDNA results and subsequent management. Finally, knowledge gaps and areas for further study are discussed.

Key Points: Twenty-five percent of those with unexplained kidney failure have a monogenic cause. Whole genome sequencing with broad gene panel analysis is a feasible diagnostic approach in nephrology. Background: The cause of kidney failure is unknown in approximately 10% of patients with stage 5 chronic kidney disease (CKD). For those who first present to nephrology care with kidney failure, standard investigations of serology, imaging, urinalysis, and kidney biopsy are limited differentiators of etiology. We aimed to determine the diagnostic utility of whole genome sequencing (WGS) with analysis of a broad kidney gene panel in patients with kidney failure of unknown cause. Methods: We prospectively recruited 100 participants who reached CKD stage 5 at the age of ≤50 years and had an unknown cause of kidney failure after standard investigation. Clinically accredited WGS was performed in this national cohort after genetic counseling. The primary analysis was targeted to 388 kidney-related genes with second-tier, genome-wide, and mitochondrial analysis. Results: The cohort was 61% male and the average age of participants at stage 5 CKD was 32 years (9 months to 50 years). A genetic diagnosis was made in 25% of participants. Disease-causing variants were identified across autosomal dominant tubulointerstitial kidney disease (6), glomerular disorders (4), ciliopathies (3), tubular disorders (2), Alport syndrome (4), and mitochondrial disease (1). Most diagnoses (80%) were in autosomal dominant, X-linked, or mitochondrial conditions (UMOD; COL4A5; INF2; CLCN5; TRPC6; COL4A4; EYA1; HNF1B; WT1; NBEA; m.3243A>G). Participants with a family history of CKD were more likely to have a positive result (odds ratio, 3.29; 95% confidence interval, 1.10 to 11.29). Thirteen percent of participants without a CKD family history had a positive result. In those who first presented in stage 5 CKD, WGS with broad analysis of a curated kidney disease gene panel was diagnostically more informative than kidney biopsy, with biopsy being inconclusive in 24 of the 25 participants. Conclusions: In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.

In a prospective study of solid-organ transplant recipients ( n = 22; 15 hepatic and 7 renal) receiving valganciclovir for cytomegalovirus (CMV) prophylaxis, electronic estimation of glomerular filtration rate (eGFR) underestimated the true GFR (24-h urine creatinine clearance) by >20% in 14/22 (63.6%). Its use was associated with inappropriate underdosing of valganciclovir, while the Cockroft-Gault equation was accurate in 21/22 patients (95.4%). Subtherapeutic ganciclovir levels (≤0.6 mg/liter) were common, occurring in 10/22 patients (45.4%); 7 had severely deficient levels (<0.3 mg/liter).

We present a kidney-pancreas transplant recipient who achieved complete recovery from COVID-19. A 45-year-old patient with T3 paraplegia underwent kidney-pancreas transplantation 18 years ago, followed by a subsequent kidney transplant 9 years ago, and presented with fever, hypoxia and hypotension after exposure to two confirmed cases of COVID-19. History of solid organ transplant, pre-existing renal impairment, asthma and an elevated D-dimer were identified as established risk factors for severe COVID-19. Supportive management was provided, baseline immunosuppression with everolimus was continued, and oral prednisolone was increased. A complete recovery was observed. Given the favourable outcome despite risk factors for severe COVID-19, we identify and review the potential mitigating roles of immunosuppression and mammalian target of rapamycin (mTOR) inhibitors in this disease. Further investigation is required to establish whether mTOR inhibitors could be used as therapeutic agents to treat COVID-19, or as alternative immunosuppression implemented early in the COVID-19 disease course.

De novo blood donor-specific human leukocyte antigen (HLA) antibodies (bDSA) from red cell transfusions can complicate solid organ transplantation, but the incidence rate is uncertain. We conducted a prospective observational study to assess the cumulative incidence rate of de novo bDSA in a cohort of patients with chronic kidney disease and no prior transplant, patients with prior kidney transplants (with or without continuing immunosuppression), and a general patient population. HLA antibody testing was performed before and 6 to 8 weeks after transfusion, with patient and blood donor typing. De novo HLA class 1 bDSA were detected in 10.8% (12 of 111) participants at a "weak" cutoff and in 7.2% (8 of 111) at a "moderate/strong" cutoff. De novo HLA class 2 bDSA were detected in 0.9% (1 of 111) at both cutoffs. Risk factors identified for HLA class 1 de novo bDSA included female sex (P < .001) and pretransfusion HLA antibodies (P = .02). The posttransplant group had low de novo bDSA (1 of 37, 2.7%). Additional testing suggested anamnestic (rather than de novo) responses in some participants. Red cell transfusions are associated with de novo bDSA, especially to HLA class 1 antigens, and measures to prevent sensitization, including selecting donors to avoid mismatches, may be warranted for some groups.