Uremic State Research Articles

Saliva as an alternative to blood in the determination of uremic state in adult patients with chronic kidney disease: a systematic review and meta-analysis.

To assess whether salivary urea and creatinine levels accurately reflect their serum levels in blood samples of adults to detect chronic kidney disease. A systematic review was conducted in eight electronic databases. The protocol was registered in PROSPERO. Only diagnostic test studies were included. The JBI critical appraisal tools assessed the risk of bias. A meta-analysis of proportions was performed. The GRADE tool assessed the quality of evidence and strength of recommendation across the studies included. Eight studies met the eligibility criteria and were included. Six studies assessed salivary urea, and six studies assessed salivary creatinine. All studies presented moderate risk of bias. The meta-analysis depicted an overall sensitivity of 93.3% (95% CI = 88.6; 97.9) for salivary creatinine levels and 87.5% (95% CI = 83.2; 91.8) for salivary urea levels, while the overall specificity was 87.1% (95% CI = 82.8; 91.3) and 83.2% (95% CI = 65.0; 101.4) for salivary creatinine and urea levels, respectively. The overall accuracy of salivary creatinine was 5.2 percentage points higher compared with salivary urea levels (90.8% vs. 85.6%). According to the GRADE tool, the analysed outcomes were classified as having low tomoderate level of certainty. Compared with blood samples, salivary urea and creatinine levels presented high diagnostic values for chronic kidney disease screening, but should not be considered equivalent to levels obtained from blood at stages three, four, or five of the disease. Chronic kidney disease patients could receive a clinically significant benefit from replacing blood with saliva for potentially monitoring renal function. Saliva collection presents greater simplicity, comfort, safety, and lower collection cost.

Synaptic plasticity in hippocampal CA1 neurons and learning behavior in acute kidney injury, and estradiol replacement in ovariectomized rats

BackgroundNeurological complications may occur in patients with acute or chronic renal failure; however, in cases of acute renal failure, the signs and symptoms are usually more pronounced, and progressed rapidly. Oxidative stress and nitric oxide in the hippocampus, following kidney injury may be involved in cognitive impairment in patients with uremia. Although many women continue taking hormone therapy for menopausal symptom relief, but there are also some controversies about the efficacy of exogenous sex hormones, especially estrogen therapy alone, in postmenopausal women with kidney injury. Herein, to the best of our knowledge for the first time, spatial memory and synaptic plasticity at the CA1 synapse of a uremic ovariectomized rat model of menopause was characterized by estradiol replacement alone.ResultsWhile estradiol replacement in ovariectomized rats without uremia, promotes synaptic plasticity, it has an impairing effect on spatial memory through hippocampal oxidative stress under uremic conditions, with no change on synaptic plasticity. It seems that exogenous estradiol potentiated the deleterious effect of acute kidney injury (AKI) with increasing hippocampal oxidative stress.ConclusionsAlthough, estrogen may have some positive effects on cognitive function in healthy subjects, but its efficacy in menopause subjects under uremic states such as renal transplantation, needs to be further investigated in terms of dosage and duration.

Nilai rasio netrofil limfosit dan rasio trombosit limfosit pada pasien chronic kidney disease sebelum dan setelah hemodialisa

Background: CKD is a world health problem with an increasing incidence, having a poor prognosis and requiring expensive treatment costs. Cardiovascular disease is the cause of high mortality rates in CKD patients due to inflammation. Neutrophil to lymphocytes ratio (NLR) and platelet to lymphocyte ratios (PLR) are considered as inflammatory markers that are cheap, fast and easily calculated from the routine blood examination. This study aimed to know the value of RNL and RTL in CKD patients before and after HD as the initial marker of inflammation. Method: Eighty-eight patients with CKD were divided into three groups before HD, after the first HD, and after the third HD. The neutrophil-lymphocyte ratio and platelet-lymphocyte ratio are calculated based on the results of routine blood tests. Data distribution was tested with Kolmogorov-Smirnov and analyzed by appropriate data testing.Results: RNL and RTL values in CKD patients after HD increased compared to before HD (p <0.05). There is a weak correlation between RNL values and serum urea levels. However, the RTL value only correlates with urea before hemodialysis.Conclusion: There are differences in RNL and RTL values in CKD patients before HD, after the first HD and third HD. There is a correlation between the RNL value and the state of uremia that is aggravated by HD

PH Grand Rounds: A Case of Pulmonary Hypertension Associated With High Cardiac Output State from Arteriovenous Fistula–Or Is It?

PH Grand Rounds: A Case of Pulmonary Hypertension Associated With High Cardiac Output State from Arteriovenous Fistula–Or Is It?

Mild cognitive impairment and kidney disease: clinical aspects.

A link between brain dysfunction and advanced kidney disease was first noted in the 1930s. Terms such as “uremic encephalopathy”, “dialysis disequilibrium syndrome” and “dialysis dementia” were later used to describe impairment of brain function in severe uremic states or during the rapid initiation of early dialysis regimens. Recent data, however, suggest brain damage can be present at earlier stages in chronic kidney disease (CKD), and manifest with a continuum from mild involvement (mild cognitive impairment, MCI) up to clinically relevant dementia. Being a prodromal stage, MCI should be identified and studied before irreversible damage is present. MCI is detectable in up to 30-60% of patients with mild CKD (MCI-CKD). Brain imaging and electrophysiological studies suggest that MCI-CKD represents a more complex clinical entity different in many ways from MCI seen in the general population, which is more often age-related and linked to widespread vascular disease. Moreover, even hemodialysis regimens used today appear unable to prevent MCI-CKD, and may even worsen it, whereas kidney transplantation seems to limit disease progression. This suggests that factors not fully correctable by dialysis, including uncleared “middle molecules”, inadequately controlled hyperparathyroidism or chronic anemia, may contribute to impaired cognition. Furthermore, MCI-CKD is not only related to a reduced glomerular filtration rate (GFR) and/or the presence of albuminuria, but also carries an increased mortality risk. Most current observations are drawn from retrospective data and based on comparisons made across different studies. However, new tools now available in neuroscience (fMRI, brain tractography, two-photon microscopy, high-throughput robotic analysis of neuronal cultures) hold the promise of better insights into the characterization of MCI-CKD, its pathogenesis, and potential biomarkers.

Gut Microbiota In Chronic Kidney Disease

Abstract In health, the relationship between gut microflora and the host is of a mutualistic kind. Microbiota offers many benefits to the host, including harvesting energy, regulating host immunity, and the synthesis of vitamins. Alteration in gut microflora can lead to homeostasis disruption and development of various diseases. Dysbiosis is commonly observed in chronic kidney disease (CKD). Nutrient processing by gut microbiota results in the production of some uremic toxins, and these accumulate in CKD causing deleterious effects. Increased permeability of the intestinal barrier, which is also seen in CKD contributes to the development of the uremic state. These factors are associated with chronic inflammation and oxidative stress and therefore are involved in CKD-related complications, including disease progression, cardiovascular disease, anemia, mineral-metabolism, and insulin resistance. This review describes connections between altered gut microflora and development of CKD and its complications, as well as possible therapeutic options. 1. Microbiota – short characteristic. 2. Mechanisms leading to alterations in gut microbiota and their effects on intestinal barrier permeability. 3. Causes of chronic kidney disease progression related to gut microbiota alterations. 4. Complications of chronic kidney disease related to gut microbiota alterations. 4.1. Cardiovascular disease. 4.2. Anemia. 4.3. Bone metabolism disorders. 4.4. Insulin resistance in CKD. 5. Therapeutic options. 6. Summary

Endothelial cells exposed to phosphate and indoxyl sulphate promote vascular calcification through interleukin-8 secretion.

Vascular calcification (VC) is amplified during chronic kidney disease, partly due to uraemic toxins such as inorganic phosphate (Pi) and indoxyl sulphate (IS) that trigger osteogenic differentiation of vascular smooth muscle cells (VSMCs). These toxins also alter endothelial cell (EC) functions but whether this contributes to VC is unknown. Here, we hypothesized that ECs exposed to Pi and IS promote VSMC calcification. Human umbilical vein ECs were treated with Pi, IS or both, and then the conditioned media [endothelial cell conditioned medium (EC-CM)] was collected. Human aortic SMCs (HASMCs) were exposed to the same toxins, with or without EC-CM, and then calcification and osteogenic differentiation were evaluated. Procalcifying factors secreted from ECs in response to Pi and IS were screened. Rat aortic rings were isolated to assess Pi+IS-induced calcification at the tissue level. Pi and Pi+IS induced HASMCs calcification, which was significantly exacerbated by EC-CM. Pi+IS induced the expression and secretion of interleukin-8 (IL-8) from ECs. While IL-8 treatment of HASMCs stimulated the Pi+IS-induced calcification in a concentration-dependent manner, IL-8 neutralizing antibody, IL-8 receptors antagonist or silencing IL-8 gene expression in ECs before collecting EC-CM significantly prevented the EC-CM procalcifying effect. IL-8 did not promote the Pi+IS-induced osteogenic differentiation of HASMCs but prevented the induction of osteopontin (OPN), a potent calcification inhibitor. In rat aortic rings, IS also promoted Pi-induced calcification and stimulated the expression of IL-8 homologues. Interestingly, in the Pi+IS condition, IL-8 receptor antagonist lifted the inhibition of OPN expression and partially prevented aortic calcification. These results highlight a novel role of IL-8, whose contribution to VC in the uraemic state results at least from interaction between ECs and VSMCs.

Regenerative potential of induced pluripotent stem cells derived from patients undergoing haemodialysis in kidney regeneration

Kidney regeneration from pluripotent stem cells is receiving a lot of attention because limited treatments are currently available for chronic kidney disease (CKD). It has been shown that uremic state in CKD is toxic to somatic stem/progenitor cells, such as endothelial progenitor and mesenchymal stem cells, affecting their differentiation and angiogenic potential. Recent studies reported that specific abnormalities caused by the non-inherited disease are often retained in induced pluripotent stem cell (iPSC)-derived products obtained from patients. Thus, it is indispensable to first assess whether iPSCs derived from patients with CKD due to non-inherited disease (CKD-iPSCs) have the ability to generate kidneys. In this study, we generated iPSCs from patients undergoing haemodialysis due to diabetes nephropathy and glomerulonephritis (HD-iPSCs) as representatives of CKD-iPSCs or from healthy controls (HC-iPSCs). HD-iPSCs differentiated into nephron progenitor cells (NPCs) with similar efficiency to HC-iPSCs. Additionally, HD-iPSC-derived NPCs expressed comparable levels of NPC markers and differentiated into vascularised glomeruli upon transplantation into mice, as HC-iPSC-derived NPCs. Our results indicate the potential of HD-iPSCs as a feasible cell source for kidney regeneration. This is the first study paving the way for CKD patient-stem cell-derived kidney regeneration, emphasising the potential of CKD-iPSCs.

Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease

The high serum fibroblast growth factor 23 (FGF23) levels in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased morbidity and mortality. Mice with folic acid-induced AKI had an increase in bone FGF23 mRNA expression together with an increase in serum FGF23 and several circulating cytokines including interleukin-6 (IL-6). Dexamethasone partially prevented the increase in IL-6 and FGF23 in the AKI mice. IL-6 knock-out mice fed an adenine diet to induce CKD failed to increase bone FGF23 mRNA and had a muted increase in serum FGF23 levels, compared with the increases in wild-type mice with CKD. Therefore, IL-6 contributes to the increase in FGF23 observed in CKD. Hydrodynamic tail injection of IL-6/soluble IL-6 receptor (sIL-6R) fusion protein hyper IL-6 (HIL-6) plasmid increased serum FGF23 levels. Circulating sIL-6R levels were increased in both CKD and AKI mice, suggesting that IL-6 increases FGF23 through sIL-6R-mediated trans-signaling. Renal IL-6 mRNA expression was increased in mice with either AKI or CKD, suggesting the kidney is the source for the increased serum IL-6 levels in the uremic state. HIL-6 also increased FGF23 mRNA in calvaria organ cultures and osteoblast-like UMR106 cells in culture, demonstrating a direct effect of IL-6 on FGF23 expression. HIL-6 increased FGF23 promoter activity through STAT3 phosphorylation and its evolutionarily conserved element in the FGF23 promoter. Thus, IL-6 increases FGF23 transcription and contributes to the high levels of serum FGF23 in both acute and chronic kidney disease.

A novel mitochondria‐targeted hydrogen sulfide delivery molecule prevents uraemia and diabetes‐induced renal cell oxidative stress

Chronic Kidney Disease (CKD) is a disturbingly fast growing global public health problem affecting an estimated 9–16% of the world population. We and others have confirmed that cardiovascular disease is often a state of hydrogen sulfide (H2S) deficiency, coinciding with mitochondrial dysfunction and increased oxidative stress. Mitochondria‐specific H2S‐delivery molecules such as AP39 have been shown to protect the kidney during ischaemia‐reperfusion injury and during organ transplantation. Although the primary effect of endogenous and pharmacological H2S on mammalian cells appears to be overwhelmingly mitochondrial, the pathophysiological importance of mitochondrial H2S deficiency, and the potential therapeutic benefit of H2S in CKD models of uremic stress and diabetic nephropathy have not yet been explored.To elucidate the pathophysiology of CKD‐induced uremic stress, we first investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on the production of reactive oxygen species (‘ROS’) in multiple immortalised glomerular cell lines (glomerular endothelial cell [GEnCs], podocytes [PODs], and proximal tubule epithelial cells [PTECs]). Furthermore, we investigated the effects of mitochondria‐targeted H2S delivery molecules on IS‐induced ‘ROS’ production. Preliminary data showed that IS increased ‘ROS’ production in PODs and PTECs (100 μg/ml; P<0.05) and that the mitochondria‐targeted H2S delivery molecule AP39 (100nM) at least partially prevented this. We also investigated the effect of IS treatment on cell death, and whether AP39 was able to prevent this. IS (100ug/ml) induced significant cell death after 24 hrs treatment in both GEnCs and PODs, which was prevented by treatment with AP39 (100nM) (P<0.05). In addition to this, we found that AP39 increased the phosphorylation (Ser453) of the cytoprotective AKT in GEnCs exposed to diabetic and uremic stress. AP39 also prevented the mitochondria‐cytoplasmic translocation of the pro‐apoptotic factor cytochrome c in diabetic and uremic‐stressed GEnCs (P<0.05).These preliminary data indicate that uremic states may deteriorate renal function via mitochondrial dependent oxidative stress, which could be prevented by therapeutic H2S delivery. Indeed, the mitochondrial ROS generation, cell death, and cytochrome c release into the cytoplasm by uremic toxins and a diabetic environment in renal cells were, at least in part, reversed by AP39. Further studies are currently underway to determine whether mitochondrial H2S deficiency could be a novel clinically applicable target for treatment in (chronic) kidney disease.Support or Funding InformationBritish Heart Foundation and MRC funded research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Sodium Thiosulfate on Arterial Stiffness in End-Stage Renal Disease Patients Undergoing Chronic Hemodialysis (Sodium Thiosulfate-Hemodialysis Study): A Randomized Controlled Trial

Background: Arterial stiffness (AS) and vascular calcification are significantly related to a high cardiovascular mortality risk in hemodialysis (HD) patients. Intravenous sodium thiosulfate (IV STS) can prevent and delay the vascular calcification progression in uremic states; however, the STS effect on AS has not been assessed. This study aimed to evaluate the STS efficacy on vascular calcification and AS in HD patients. Methods: Fifty HD patients with abnormal AS, as measured via the cardio-ankle vascular index (CAVI ≥8), were prospectively randomized to open-label 12.5 g IV STS during the last HD hour twice weekly for 6 months (n = 24) or the usual care (control group; n = 26). Patients and treating physicians were not blinded. The CAVI, coronary artery calcification (CAC) score, hemodynamics, and biochemical parameters were measured at the baseline and at 3 and 6 months. Results: All the baseline parameters were comparable. The IV STS significantly reduced the CAVI when compared to the control group (mean CAVI difference = –0.53; 95% CI –1.00 to –0.06; p = 0.03). A significant CAVI improvement was seen in those patients without diabetes mellitus. The natural logarithm of the CAC volume score was significantly increased in the control group. The high sensitivity C-reactive protein level was slightly lowered in the IV STS group (not significant). Conclusion: The intradialytic STS treatment significantly reduced the AS, as measured by the CAVI, and stabilized the vascular calcification in the HD patients. STS may be a novel therapeutic strategy for delaying and treating the structural and functional vascular wall abnormalities in HD patients.

Assessment of oral manifestations of patients with renal failure undergoing hemodialysis by serum and salivary biomarkers

Background: Renal failure refers to a condition where the kidneys lose their normalfunctionality. Patients with end stage renal disease (ESRD) have to undergohemodialysis (HD), With impaired renal function, a decreased glomerularfiltration rate (GFR), and the accumulation and retention of various products ofrenal failure, the oral cavity may show a variety of changes as the body progressesthrough an azotemic to a uremic state. The general dentist should be able torecognize these oral symptoms as part of the patient’s systemic disease and not asan isolated occurrence.Aims of the study: To evaluate the biochemical properties of the saliva andAssessment of oral manifestations in patients with chronic renal failureundergoing hemodialysis.Patients and methods: Spectrophotometer was used for measuring serum andsalivary calcium, phosphorous, urea and creatinine in thirty three hemodialysispatients and twenty two control healthy subjects . Salivary PH, Gingival indexand salivary buffering capacity was also recorded.Results and discussion: All serum and salivary biomarkers (calcium, phosphorous,urea and creatinine) were significantly changed in hemodialysis patients (calciumdecreased while the others increased).Also salivary PH and buffering capacitywere significantly increased in hemodialysis patients. Gingival index alsoincreased, and the oral manifestations that was recorded include: dry mouth(n=21), uremic odor (n=20) , bad taste (n=17) , burning sensation (n=14) , coatedtongue (n=10) ,pale mucosa ( n=5) petechia (n=3), fissured tongue (n=3).Conclusions: there was differences in salivary parameters between hemodialysispatients and control group and the salivary variables was correlated too serumvariables , many oral manifestations found to be in hemodialysis patients.

Defective interplay between mTORC1 activity and endoplasmic reticulum stress-unfolded protein response in uremic vascular calcification.

Vascular calcification increases the risk of cardiovascular disease and death in patients with chronic kidney disease (CKD). Increased activity of mammalian target of rapamycin complex 1 (mTORC1) and endoplasmic reticulum (ER) stress-unfolded protein response (UPR) are independently reported to partake in the pathogenesis of vascular calcification in CKD. However, the association between mTORC1 activity and ER stress-UPR remains unknown. We report here that components of the uremic state [activation of the receptor for advanced glycation end products (RAGE) and hyperphosphatemia] potentiate vascular smooth muscle cell (VSMC) calcification by inducing persistent and exaggerated activity of mTORC1. This gives rise to prolonged and excessive ER stress-UPR as well as attenuated levels of sestrin 1 ( Sesn1) and Sesn3 feeding back to inhibit mTORC1 activity. Activating transcription factor 4 arising from the UPR mediates cell death via expression of CCAAT/enhancer-binding protein (c/EBP) homologous protein (CHOP), impairs the generation of pyrophosphate, a potent inhibitor of mineralization, and potentiates VSMC transdifferentiation to the osteochondrocytic phenotype. Short-term treatment of CKD mice with rapamycin, an inhibitor of mTORC1, or tauroursodeoxycholic acid, a bile acid that restores ER homeostasis, normalized mTORC1 activity, molecular markers of UPR, and calcium content of aortas. Collectively, these data highlight that increased and/or protracted mTORC1 activity arising from the uremic state leads to dysregulated ER stress-UPR and VSMC calcification. Manipulation of the mTORC1-ER stress-UPR pathway opens up new therapeutic strategies for the prevention and treatment of vascular calcification in CKD.

Evaluation of Vitamin A and e levels in Chronic Renal Failure

Any atom or molecule that contains one or more unpaired electrons is defined as free radical, the most known reactive species. An unpaired electron is an electron that occupies an orbital alone, but electrons usually associate in pairs in orbital's of atoms and molecules. The present study focuses on the extent of free radical damage on lipid and Lipid peroxidation end products (measured as malondialdehyde, MDA) and effect on antioxidant defense mechanism (measured as vitamin E and vitamin C in the serum of CRF patients predialytically. The study was Carried in Sri Lakshmi narayana Institute of Medical Sciences, Pondicherry. 50 cases and 50 controls between age group of 30–60 were taken. Lipid peroxidation was measured in terms of MDA and antioxidants were measured as vitamin E and Vitamin C in serum of CRF patients before dialysis. The level of MDA, serum urea and Creatinine was significantly increased, antioxidant vitamin levels (C and E) were decreased in CRF patients as compared to normal subjects. Though there is evidence for production of oxygen free radicals in CRF, reports on net oxidative imbalance in the uremic state, as evidenced by increase in oxidant markers and decrease in antioxidant vitamins status in CRF patients. Oxidative injury generally takes place only when local oxidant production exceeds antioxidant defense.

The Effect of Biliary Drenage on Uremic State

The Effect of Biliary Drenage on Uremic State

Intensive nutritional counselling obviates a weight gain in kidney transplant recipients with long-term graft survival in Estonia

Background. After kidney transplantation body weight gain (WG) in patients generally increases and this can be influenced by improved appetite and reversal of the uremic state. Because of a lack of evidence for effective interventions that prevent body WG after kidney transplantation, Ryan et al. recently published a randomized controlled trial design in BMC Nephrology to assess the effects of intensive nutrition interventions on WG and metabolic parameters. Here we are demonstrating a part of a study performed at our transplantation centre where we also performed an intensive nutritional counselling intervention on kidney recipients. We hypothesised that kidney transplant (KTx) patients who received intensive counselling may have better long-term weight control compared with patients who did not receive such counselling. Methods. During intensive counselling the dietician took into consideration the results of anthropometry, densitometry, biochemistry, food frequency questionnaire and an analysis of 3-day dietary records. Anthropometrical measurements were assessed at 18 months, 36 months, and, finally, 10 years after the kidney transplantation. Results. We noticed WG in all KTx patients (n=56) both in males and females, as follows: in the standard care group the mean WG in males (N=21) was 6.4 kg, females (N=15) 7.0 kg and among intensively counselled males (N=9) 4.6 kg, females (N=11) 1.1 kg. Statistically non-significant weight change was found among counselled living KTx patients with long-term graft survival both in males (p=0.0680) and females ( p=0.3166) which was registered 10 years after the KTx compared with the first measurement mean weight. Among standard care control KTx patients, weight change was statistically significant in both males and females (males: p=0.0016; females: p=0.0040) 10 years after the KTx. Conclusions. The long-term WG data clearly showed that in our population of KT patients, the patients who received intensive individual dietary counselling had much more educated behaviour in the long-term, thereby preventing WG which is a well-known risk factor for long-term graft failure as well as for cardiovascular complications and mortality.

The Influence of Hemodialysis on T Regulatory Cells: A Meta-Analysis and Systematic Review

Aims: The study aimed to determine whether the available literature supports a positive or negative influence of dialysis on regulatory T-cells (Tregs). Methods: We performed a systematic search and a meta-analysis. Mean differences in Tregs number of chronic kidney disease stages G5 on dialysis patients (CKD G5D) and healthy controls (HCs) were compared. Random effects model was applied. The software used was general package for meta-analysis (version 4.3-0, depends R (≥2.9.1)). Results: Five studies were included in the meta-analysis. The mean difference in percentage of Tregs on CD4+ T-cells between CKD G5D and HCs was not statistically different. Moreover, CKD GFR stages G5 not on dialysis (CKD G5) versus HC (p = 0.002; mean difference in Treg percentage was -2.47% in CKD G5 vs. HC) and CKD G5 versus CKD G5D (not significant). Conclusion: This meta-analysis demonstrates an association between the uremic state and lower Tregs, and supports the hypothesis that hemodialysis alter Tregs. Our findings highlight the need for new clinical studies. Video Journal Club ‘Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=449242.

Left atrial and ventricular systolic and diastolic myocardial mechanics in patients with end-stage renal disease.

Diastolic cardiac dysfunction is an important complication of end-stage renal disease (ESRD), but quantification remains a challenge. Given that diastolic dysfunction is reflected in both left atrial (LA) and ventricular (LV) function, we aimed to identify abnormalities in LV and LA volume and function using measures of myocardial mechanics. We retrospectively studied 53 incident ESRD patients (46±16y/o 44% male) and compared them to 85 normal controls. LA phasic volumes and functional parameters were obtained from the apical 4CH view. Global ventricular peak longitudinal and circumferential strain, strain rate (GLS, GL-SR, CS), and rotation were obtained from apical and short-axis views. LA and LV measurements were taken off line using dedicated software (eSie VVI). ESRD patients had abnormal systolic function with lower LV ejection fraction and peak endocardial strain parameters (mean: GLS -16.6% vs -19.9%, GL-SR -0.91 vs -1.04, and CS -25.6% vs 27.9%, P≤.01 for all). Traditional Doppler parameters remained similar between groups, while diastolic mechanics were abnormal in ESRD. Reduced LV-derived diastolic parameters, fractional early reverse rotation, a marker of ventricular relaxation (P<.006), and ratio of early diastolic SR to systolic SR (P<.04) denote significant diastolic dysfunction. Increased LA volumes (P<.001), decreased LA reservoir (P<.001), conduit (P<.0004), and contractile (P<.02) function reflect diastolic dysfunction. Myocardial strain measurements quantitated the abnormalities in both LV diastolic and LA function associated with the uremic state. The distinct abnormal diastolic parameters were suggestive of abnormal relaxation and increased filling pressures. Early and accurate assessment of diastolic function may help tailor patient management ESRD.

Uraemia: an unrecognized driver of central neurohumoral dysfunction in chronic kidney disease?

Chronic kidney disease (CKD) carries a large cardiovascular burden in part due to hypertension and neurohumoral dysfunction - manifesting as sympathetic overactivity, baroreflex dysfunction and chronically elevated circulating vasopressin. Alterations within the central nervous system (CNS) are necessary for the expression of neurohumoral dysfunction in CKD; however, the underlying mechanisms are poorly defined. Uraemic toxins are a diverse group of compounds that accumulate as a direct result of renal disease and drive dysfunction in multiple organs, including the brain. Intensive haemodialysis improves both sympathetic overactivity and cardiac baroreflex sensitivity in renal failure patients, indicating that uraemic toxins participate in the maintenance of autonomic dysfunction in CKD. In rodents exposed to uraemia, immediate early gene expression analysis suggests upregulated activity of not only pre-sympathetic but also vasopressin-secretory nuclei. We outline several potential mechanisms by which uraemia might drive neurohumoral dysfunction in CKD. These include superoxide-dependent effects on neural activity, depletion of nitric oxide and induction of low-grade systemic inflammation. Recent evidence has highlighted superoxide production as an intermediate for the depolarizing effect of some uraemic toxins on neuronal cells. We provide preliminary data indicating augmented superoxide production within the hypothalamic paraventricular nucleus in the Lewis polycystic kidney rat, which might be important for mediating the neurohumoral dysfunction exhibited in this CKD model. We speculate that the uraemic state might serve to sensitize the central actions of other sympathoexcitatory factors, including renal afferent nerve inputs to the CNS and angiotensin II, by way of recruiting convergent superoxide-dependent and pro-inflammatory pathways.

D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile.

Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients.