Association of Impaired Reactive Aldehyde Metabolism with Delayed Graft Function in Human Kidney Transplantation

Abstract

Delayed graft function is an early complication following kidney transplantation with an unclear molecular mechanism. Here we determined whether impaired reactive aldehyde metabolism is associated with delayed graft function. Human kidney biopsies from grafts with delayed graft function were compared with grafts that did not develop delayed graft function by Ingenuity gene pathway analysis. A second series of grafts with delayed graft function (n = 10) were compared to grafts that did not develop delayed graft function (n = 10) by measuring reactive aldehyde metabolism, reactive aldehyde-induced protein adduct formation, and aldehyde dehydrogenase (ALDH) gene and protein expression. In the first series of kidney biopsies, several gene families known for metabolizing reactive aldehydes, such as aldehyde dehydrogenase (ALDH), aldo-keto reductase (AKR), and glutathione-S transferase (GSTA), were upregulated in kidneys that did not develop delayed graft function versus those that did. In the second series of kidney grafts, we focused on measuring aldehyde-induced protein adducts and ALDH enzymatic activity. The reactive aldehyde metabolism by ALDH enzymes was reduced in kidneys with delayed graft function compared to those that did not (37 ± 12∗ vs. 79 ± 5 μg/min/mg tissue, ∗ P < 0.005, respectively). ALDH enzymatic activity was also negatively correlated with length of hospital stay after a kidney transplant. Together, our study identifies a reduced ALDH enzymatic activity with kidneys developing delayed graft function compared to those that did not. Measuring ALDH enzymatic activity and reactive aldehyde-induced protein adducts can potentially be further developed as a biomarker to assess for delayed graft function and recovery from a kidney transplant.

Acidosis and alkali therapy in patients with kidney transplant is associated with transcriptional changes and altered abundance of genes involved in cell metabolism and acid–base balance

“…The same observations has been made in several animal models of kidney disease [8,9]. A similar effect has been reported in patients with kidney transplant and consuming a Mediterranean diet [10]. Experiments in animals suggested that a variety of mechanisms could contribute to the protective effects of alkali therapy or to enhance kidney damage in acidosis.…”

Utility of SIFT-MS to evaluate volatile organic compounds in nephropathic patients’ breath

“…As proof of this, an ALDH2 deficiency increases the ROS production, causes the accumulation of 4-hydroxynonenal (a reactive aldehyde able to inhibit the ALDH enzymes), provokes oxidative damage to DNA and promotes apoptosis of renal tubular epithelial cells 47 . An altered metabolism of reactive aldehydes (namely acetaldehyde, malonyldialdehyde, 4-hydroxynonenal) is associated with the development delayed graft function (DGF) in kidney transplanted patients 48 , since it involves the formation of aldehyde adducts on proteins that can alter cellular functions by inducing changes of the enzymatic activity, of ion channels and of mitochondrial energetic pathways 49 . Therefore, the increase in acetaldehyde that we observed in CKD patients could be related to the oxidative stress that characterizes the disease itself 50 .…”

Pretransplant endotrophin predicts delayed graft function after kidney transplantation

“…A systematic review showed that risk prediction models for DGF commonly include recipient age and comorbidities 5 . Although several causes and mechanisms leading to DGF have been described in the last years, therapeutic or preventive options are still limited 6 , 7 .…”