Possibility of Functional Restoration of HDL

HDL function has been a recent focus of experimental research. With respect to weak effects on cardiovascular outcome after an increase of HDL quantity in CKD patients, HDL function capacity appears important for the design of new therapeutic approaches. Therefore, the question arose whether structural modifications and associated dysfunctions under uremic conditions are reversible. The best approach to test this hypothesis in the case of renal function is to study patients after successful renal transplantation. A limitation of this model is that these patients often require immunosuppressive drugs, which may affect lipid metabolism and function (Badiou et al. 2009). Some investigations have attempted to observe changes in HDL function after renal transplantation. Dantoine and coworkers reported that the PON enzyme activity in patients after kidney transplantation was comparable to that in control subjects, whereas in dialysis patients, it was decreased (Dantoine et al. 1998). Furthermore, the anti-inflammatory capacity of HDL from ESRD patients compared with healthy controls increased after successful renal transplantation (van der Giet et al. 2010b). The observed effect appears to be related to a decreased SAA level in transplant recipients. Other indicators of the reversibility of HDL dysfunction are based on studies with chronic heart failure patients. In this cohort, exercise training, which is an accepted intervention strategy to decrease cardiovascular risk in heart failure patients, resulted in increased HDL. The authors demonstrated that changes in HDL function induced by exercise training correlated with improved endothelial function (Adams et al. 2013).

According to these data it has been suggested that a restoration of HDL is possible. The lipid metabolism and the composition of different lipoprotein particles are primarily influenced by the metabolic condition. To date, little information is available regarding whether the CKD stage before transplantation is dependent on the HDL functionality after kidney transplantation or whether a point-of-no-return exists for functional restoration, vessel damage, and cardiovascular risk.

Laboratory Tests to Measure HDL Function

According to previous clinical and experimental trials, it has become clear that HDL particle modifications in disease conditions are associated with reduced HDL function; specific factors that determine HDL functionality remain unclear. It is known that various structural features are associated with HDL function, which can be measured by in vitro studies. A limitation arises in the difficulty of comparing experimental results. The standardization of the experimental design for HDL isolation, separation of proteins/lipids, sample preparation for proteomic approaches, and detection methods for components within HDL would help to overcome certain limitations that may result in discrepancies between findings. In addition, in vitro functionality assays are very complex and further hamper comparability. The complexity and cost preclude these tests from routine clinical laboratory analyses, thus limiting the validation of experimental findings of functionality in large clinical trials. Standardization, validation, and optimization for high throughput must first be established.

Recently, an overview of the laboratory tests that measure HDL subclasses (shape, density) and several HDL functions was described (Eren et al. 2012). There is a growing need to identify an optimal biomarker that describes HDL functionality. The development of reproducible, standardized, and validated methods to assess HDL function for routine use is of substantial interest. The knowledge regarding individual HDL function can help identify patients who may benefit from HDL-C increasing therapy or patients with a normal HDL-C level but at particularly high risk for cardiovascular events.

HDL is a plasma lipoprotein with many pleiotropic protective functions in the vascular wall, including anti-atherosclerotic properties. Emerging evidence from clinical and laboratory studies indicates that HDL-C plasma levels in humans do not adequately represent HDL function. The pleiotropic protective effects of HDL depend on its composition, which is influenced by pathophysiological conditions. With the decline of renal function, HDL modifications occur. Evidence suggests that HDL composition, rather than plasma level, may be an important determinant for its pleiotropic protective function in the vascular wall. The goal is to identify robust biomarkers that describe HDL functionality and are measurable in validated, standardized assays that can be used routinely. Improvement of HDL functionality may serve as an interesting therapeutic target in the future for populations beyond CKD patients.

Acknowledgements The authors thank Jaqueline Herrmann for proofreading the manuscript.

The research projects of the authors are supported by the EFSD/Boehringer Ingelheim award (M.vdG), the Hans und Gertie Fischer-Stiftung (M.T), and the Peter und Traudl Engelhorn Stiftung scholarship (M.S). M.vdG is a member of the European Cooperation in Science and Technology (COST) Action “HDLnet” (BM904).

Conflict of Interest Statement None declared.

 
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