Post-translational modifications (PTMs) of proteins and peptides have recently gained much attention, as they are involved in the pathogenesis of cardiovascular disease and eventually also play a role in the progression of chronic kidney disease (CKD). In this review, we provide an overview of post-translational protein modifications such as carbamylation, glycation and oxidation, starting with their definitions, mechanisms and clinical relevance in the setting of CKD and cardiovascular disease. The methods currently used for the identification and, in particular, quantification of PTMs are described and potential treatment options in the context of PTMs are reviewed. We foresee that advancements in mass spectrometry-based methods leading to the identification of novel disease markers and/or pathophysiologically relevant factors will certainly boost the clinical utility in sample analyses.

Chronic kidney disease (CKD), diabetes mellitus (DM), and cardiovascular diseases (CVD) are complex disorders of partly unknown genesis and mostly known progression factors. CVD and DM are the risk factors of CKD and are strongly intertwined since DM can lead to both CKD and/or CVD, and CVD can lead to kidney disease. In recent years, our knowledge of CKD, DM, and CVD has been expanded and several important experimental, clinical, and epidemiological associations have been reported. The tight cellular and molecular interactions between the renal, diabetic, and cardiovascular systems in acute or chronic disease settings are becoming increasingly evident. However, the (patho-) physiological basis of the interactions of CKD, DM, and CVD with involvement of multiple endogenous and environmental factors is highly complex and our knowledge is still at its infancy. Not only single pathways and mediators of progression of these diseases have to be considered in these processes but also the mutual interactions of these factors are essential. The recent advances in proteomics and integrative analysis technologies have allowed rapid progress in analyzing complex disorders and clearly show the opportunity for new efficient and specific therapies. More than a dozen pathways have been identified so far, including hyperactivity of the renin–angiotensin (RAS)–aldosterone system, osmotic sodium retention, endothelial dysfunction, dyslipidemia, RAS/RAF/extracellular-signal-regulated kinase pathway, modification of the purinergic system, phosphatidylinositol 3-kinase (PI 3-kinase)-dependent signaling pathways, and inflammation, all leading to histomorphological alterations of the kidney and vessels of diabetic and non-diabetic patients. Since a better understanding of the common cellular and molecular mechanisms of these diseases may be a key to successful identification of new therapeutic targets, we review in this paper the current literature about cellular and molecular mechanisms of CKD.

We used a mass spectrometry-based method for the characterization of post-translational modification and demonstrated the pathophysiological impact of a representative post-translational modification of plasma albumin. The data described in this study may help to elucidate the pathophysiological role of protein modifications.

Protein-bound uremic retention solutes accumulate in patients suffering from chronic kidney disease, and the removal of these solutes by hemodialysis is hampered. Therefore, we developed a dialysis technique where the protein-bound uremic retention solutes are removed more efficiently under high ionic strength. Protein-bound uremic solutes such as phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate were combined with plasma in the presence of increased ionic strength. The protein integrity of proteins and enzymatic activities were analyzed. In vitro dialysis of albumin solution was performed to investigate the clearance of the bound uremic retention solutes. In vitro hemodiafiltrations of human blood were performed to investigate the influence of increased ionic strength on blood cell survival. The protein-bound fraction of phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate was significantly decreased from 59.4% ± 3.4%, 95.7% ± 0.6%, 96.9% ± 1.5% to 36.4% ± 3.7%, 87.8% ± 0.6%, and 90.8% ± 1.3%, respectively. The percentage of phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate released from protein was 23.0% ± 5.7%, 7.9% ± 1.1%, and 6.1% ± 0.2%, respectively. The clearance during in vitro dialysis was increased by 13.1% ± 3.6%, 68.8% ± 15.1%, and 53.6% ± 10.2%, respectively. There was no difference in NaCl concentrations at the outlet of the dialyzer using isotonic and hypertonic solutions. In conclusion, this study forms the basis for establishing a novel therapeutic approach to remove protein-bound retention solutes.

In patients with chronic kidney disease (CKD), adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds with intrinsic biological activities, many of which are too large to be filtered and/or are protein bound. The renal excretion of protein-bound toxins depends largely on active tubular secretion, which shifts the binding and allows for active secretion of the free fraction. To facilitate this process, renal proximal tubule cells are equipped with a range of transporters that co-operate in basolateral uptake and luminal excretion. Many of these transporters have been characterized as mediators of drug disposition, but have recently been recognized for their importance in the proximal renal tubular transport of uremic toxins as well. This also indicates that during uremia, drug disposition may be severely affected as a result of drug-uremic toxin interaction. In addition, CKD patients receive various drugs to treat their complications potentially resulting in drug-drug interactions (DDIs), also for drugs that are non-renally excreted. This review discusses the current knowledge on formation, disposition and removal of protein-bound uremic toxins. Furthermore, implications associated with drug treatment in kidney failure, as well as innovative renal replacement therapies targetting the protein-bound uremic toxins are being discussed. It will become clear that the complex problems associated with uremia warrant a transdisciplinary approach that unites research experts in the area of fundamental biomedical research with their colleagues in clinical nephrology.