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      Chronic Kidney Disease (CKD) as a Systemic Disease: Whole Body Autoregulation and Inter-Organ Cross-Talk

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          The inter-organ cross-talk and the functional integration of organ systems is an exceedingly complex process which until now has been investigated with a reductionist approach. CKD perturbs the inter-organ cross-talk and demands central resetting of autonomic (nervous) control of organ systems. Due to limitations inherent to the reductionist approach, we currently identify CKD-related pseudo-syndromes and largely fail at describing the complex systemic inter-relationships set into motion by renal damage and renal dysfunction. A mature technology for a system-analysis approach to physiology and pathophysiology of CKD now exists. System biology will allow in depth understanding of complex diseases like CKD and will set the stage for predictive, preventive and personalized medicine, a long-standing dream of doctors and patients alike.

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          Most cited references 28

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          Sympathetic overactivity in patients with chronic renal failure.

          Hypertension is a frequent complication of chronic renal failure, but its causes are not fully understood. There is indirect evidence that increased activity of the sympathetic nervous system might contribute to hypertension in patients with end-stage renal disease, but sympathetic-nerve discharge has not been measured directly in patients or animals with chronic renal failure. We recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with hemodialysis (of whom 14 had hypertension), 5 patients receiving hemodialysis who had undergone bilateral nephrectomy (of whom 1 had hypertension), and 11 normal subjects. RESULTS. The mean (+/- SE) rate of sympathetic-nerve discharge was 2.5 times higher in the patients receiving hemodialysis who had not undergone nephrectomy than in the normal subjects (58 +/- 3 vs. 23 +/- 3 bursts per minute, P < 0.01). In contrast, the rate of sympathetic-nerve discharge was similar in the patients receiving hemodialysis who had undergone bilateral nephrectomy (21 +/- 6 bursts per minute) and the normal subjects. The rate of sympathetic-nerve discharge in the patients receiving hemodialysis who had not undergone nephrectomy was also significantly higher (P < 0.01) than that in the patients with bilateral nephrectomy, and it was accompanied in the former group by higher values for vascular resistance in the calf (45 +/- 4 vs. 22 +/- 4 units, P < 0.05) and mean arterial pressure (106 +/- 4 vs. 76 +/- 14 mm Hg, P < 0.05). The rate of sympathetic-nerve discharge was not correlated with either plasma norepinephrine concentrations or plasma renin activity. Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.
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            Endocrine functions of bone in mineral metabolism regulation.

             L Quarles (2008)
            Given the dramatic increase in skeletal size during growth, the need to preserve skeletal mass during adulthood, and the large capacity of bone to store calcium and phosphate, juxtaposed with the essential role of phosphate in energy metabolism and the adverse effects of hyperphosphatemia, it is not surprising that a complex systems biology has evolved that permits cross-talk between bone and other organs to adjust phosphate balance and bone mineralization in response to changing physiological requirements. This review examines the newly discovered signaling pathways involved in the endocrine functions of bone, such as those mediated by the phosphaturic and 1,25(OH)2D-regulating hormone FGF23, and the broader systemic effects associated with abnormalities of calcium and phosphate homeostasis.
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              Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach.

              High plasma asymmetrical dimethylarginine (ADMA) signals endothelial dysfunction and atherosclerosis in the general population and predicts mortality in ESRD. The relationship among plasma levels of ADMA, renal function, and the risk for progression to ESRD (halving GFR or dialysis start) and death in an incident cohort of 131 patients with chronic kidney disease was investigated. Cox's competing risk regression was used to model double-failure times (progression to ESRD and death) as a function of ADMA. Covariates that were considered for adjustment included clinical characteristics, baseline GFR (Modification of Diet in Renal Disease equation 7 formula), proteinuria, traditional cardiovascular risk factors, serum C-reactive protein, homocysteine, and concomitant therapies. Mean age at enrollment was 71 +/- 11 yr, and 24% of patients had diabetes. Baseline GFR ranged from 8 to 77 ml/min per 1.73 m2 (average 31 +/- 15 ml/min per 1.73 m2). ADMA was inversely related to GFR, ranking as the third predicting factor (partial r = -0.22, P = 0.01), after hemoglobin and urinary protein, in a general linear model that included multiple correlates of GFR. After a mean follow-up of 27 mo (range 3.4 to 36), 29 patients progressed to ESRD and 31 died. ADMA (hazard ratio per 0.1 muM/L 1.203; 95% confidence interval 1.071 to 1.350) predicted event occurrence independent of other potential confounders, including GFR, proteinuria, hemoglobin, and homocysteine. In patients with mild to advanced chronic kidney disease, plasma ADMA is inversely related to GFR and represents a strong and independent risk marker for progression to ESRD and mortality. These novel findings further expand the implications of previous observations in ESRD patients and generate hypotheses on the role of ADMA in progressive chronic nephropathies.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                August 2014
                29 July 2014
                : 39
                : 2-3
                : 134-141
                aCNR National Research Council (Italy) Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension Unit, Ospedali Riuniti Reggio Calabria, Italy; bDepartment of Nephrology Medical School, University of Ioannina Ioannina, Greece; cNephrology, Hypertension and Renal Transplantation Unit, Ospedali Riuniti Reggio Calabria, Italy
                355788 Kidney Blood Press Res 2014;39:134-141
                © 2014 S. Karger AG, Basel

                Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (, applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Pages: 8

                Cardiovascular Medicine, Nephrology

                CKD, ESRD, Phenotype, FGF23, Risk, Cardiovascular, Progression, ADMA, Sympathetic, NPY


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