In the News: Is it prime for Xenotransplantation

A seminal paper in Lancet published in 2023 focuses on the immune response after pig-to-human kidney xenotransplantation. The study uses a comprehensive approach to characterize this response in detail. 

Two pig kidney xenografts transplanted into deceased human recipients were thoroughly analyzed using various methods including morphological evaluation, immunophenotyping, gene expression profiling, digital spatial profiling, and cell deconvolution. The findings indicate early signs of antibody-mediated rejection, with evidence of microvascular inflammation, immune deposits, endothelial cell activation, and positive xeno-reactive crossmatches. The inflammation primarily consists of innate immune cells like CD68+, CD15+, and NKp46+ cells. Gene expression analysis reveals increased activation of various immune-related pathways, such as monocyte and macrophage activation, natural killer cell response, endothelial activation, complement activation, and T-cell development. 

The injury associated with antibody-mediated rejection is concentrated in the glomeruli of the xenografts, with transcripts related to monocytes, macrophages, neutrophils, and natural killer cells being significantly enriched. This rejection pattern is distinct from control autografts and ischemia-reperfusion models. The study suggests that despite initial positive outcomes, antibody-mediated rejection might still be occurring in pig-to-human kidney xenografts. The findings highlight potential therapeutic targets to address the humoral aspect of rejection and improve the success of xenotransplantation.

Interestingly, in JAMA surgery, a case report is published at the same time. The paper presents a case involving a male individual in his 50s who was declared brain dead and had acute kidney injury on top of a history of chronic kidney disease (CKD) and hypertension. After all other organ donation options were exhausted, the individual received bilateral native nephrectomy and cessation of dialysis. Crossmatch-compatible xenotransplantation was performed using 10-gene-edited pig kidneys (UKidney). The pig kidneys were modified with 10 gene changes, including knockdowns, knockouts, and human transgene insertions. The recipient was treated with a complement inhibitor (anti-C5; eculizumab) prior to xenotransplantation, followed by standard induction therapy and maintenance immunosuppression. The pig kidneys were transplanted en bloc with their vasculature anastomosed to the recipient's arteries and veins, and the ureters connected to the recipient's bladder. The pig kidneys exhibited rapid function, producing significant amounts of urine within minutes of reperfusion, and urine concentration improved over time. Serum creatinine levels dropped significantly after xenotransplantation, and creatinine clearance improved as well.

Biopsies of the xenografts showed normal histology without evidence of thrombotic microangiopathy. The authors discuss that while this case series demonstrates the success of pig-to-human xenotransplantation in providing kidney function to a deceased individual with CKD, more research with living human recipients is needed to determine the long-term function of xenograft kidneys and their potential use as a solution for the organ shortage crisis. Although single case, it highlights the potential of xenotransplantation as a viable solution for addressing the shortage of organs, which results in preventable deaths annually.

In the News: Urine Na as a marker for diuresis success

A recent editorial in JAHA discusses the use of urinary sodium (UNa) as a biomarker for monitoring and guiding diuretic therapy in patients with acute heart failure (AHF). Activation of the renin-angiotensin system in heart failure leads to sodium retention, hyperaldosteronism, and increased sympathetic activity, contributing to fluid overload. The authors highlight that assessing diuretic response through traditional methods, such as weight loss and urine volume output, can be inaccurate and logistically challenging. Instead, they propose using UNa measurements from spot urine samples taken 2 hours after diuretic administration as a more dynamic and early indicator of diuretic response.

The European Society of Cardiology (ESC) guidelines recommend using spot UNa analysis to evaluate diuretic treatment response in AHF patients. A low UNa (<50-70 mEq/L) at 2 hours post-diuretic administration is associated with inadequate diuretic response and suggests the need for more intensive diuretic therapy. The paper discusses observational studies and expert opinions that support this approach. However, it also points out limitations, such as the influence of kidney function, concurrent conditions like chronic kidney disease (CKD) and cirrhosis, and the potential loss of UNa's predictive strength after the first day of treatment due to changes in sodium excretion patterns.

The authors present data from studies that endorse the feasibility and efficacy of UNa-guided diuretic therapy in AHF. They discuss the ENACT HF trial, which showed improved natriuresis, diuresis, and shorter hospitalization duration with UNa-guided diuretic treatment. Another ongoing study, PUSH-AHF, aims to provide more definitive results on natriuresis-guided therapy using a stepwise diuretic approach.

The authors acknowledge that UNa assessment alone may not fully capture diuretic response and recommend combining UNa measurements with other indicators of decongestion, such as urine output. They also emphasize the importance of accounting for different patient factors like fluid overload status, kidney function, and the type of diuretics used.

In conclusion, while UNa-guided diuretic therapy appears promising for AHF management.. interesting and simple to do.

Love this figure from the paper