P-cresol and Indoxyl Sulfate Impair Osteogenic Differentiation by Triggering Mesenchymal Stem Cell Senescence.

Chronic kidney disease (CKD) patients obtained high levels of uremic toxins progressively develop several complications including bone fractures. Protein-bound uremic toxins especially p-cresol and indoxyl sulfate are hardly eliminated due to their high molecular weight. Thus, the abnormality of bone in CKD patient could be potentially resulted from the accumulation of uremic toxins. To determine whether protein-bound uremic toxins have an impact on osteogenesis, mesenchymal stem cells were treated with either p-cresol or indoxyl sulfate under in vitro osteogenic differentiation. The effects of uremic toxins on MSC-osteoblastic differentiation were investigated by evaluation of bone phenotype. The results demonstrated that p-cresol and indoxyl sulfate down-regulated the transcriptional level of collagen type I, deceased alkaline phosphatase activity, and impaired mineralization of MSC-osteoblastic cells. Furthermore, p-cresol and indoxyl sulfate gradually increased senescence-associated beta-galactosidase positive cells while upregulated the expression of p21 which participate in senescent process. Our findings clearly revealed that the presence of uremic toxins dose-dependently influenced a gradual deterioration of osteogenesis. The effects partially mediate through the activation of senescence-associated gene lead to the impairment of osteogenesis. Therefore, the management of cellular senescence triggered by uremic toxins could be considered as an alternative therapeutic approach to prevent bone abnormality in CKD patients.

Microbiome modulation to correct uremic toxins and to preserve kidney functions.

PURPOSE OF REVIEW: The association between dysbiosis and CKD is well established. This review focuses on the current understanding of microbiome, in normal individuals and CKD patients, in order to hypothesize how to correct uremic toxins levels and preserve the renal function and reduce associated comorbidities. Here we discuss our current opinion on microbiome modulation in order to manage the CKD-associated dysbiosis. RECENT FINDINGS: Emerging evidence confirms the role of gut microbiome in the progression of CKD. In this scenario, the need is felt to set up multifaceted approaches for dysbiosis management. Among many strategies able to improve gut wellness, a crucial approach is represented by the functional nutrition. At the same time, drug-based treatments show significant results in microbiome modulation. Furthermore, we examine here the potentialities of fecal microbiome transplantation (FMT) in CKD, an approach currently applied in Clostridium difficile infection. SUMMARY: The gut microbiome plays a pivotal role in the pathophysiology of CKD. The vicious cycle triggered by kidney function decline leads to gut dysbiosis. Considering the gut microbiome as a therapeutic target in CKD, multiple approaches aimed at its modulation should be envisioned to preserve kidney function. Dietary interventions and pharmacological strategies are able to improve microbiome dysbiosis, oxidative stress and fibrosis. Additionally, FMT could represent a promising novel therapy in the management of CKD-associated dysbiosis.

Questionable specificity of histologic findings in calcific uremic arteriolopathy.

A variety of criteria exist for histopathologic diagnosis of calciphylaxis, also known as calcific uremic arteriolopathy but data on their specificity are limited. To assess this, histologic findings of 38 skin biopsies performed for a suspicion of calcific uremic arteriolopathy were compared with histologic findings in skin obtained from healthy margins of 43 amputations in patients with end-stage renal disease (ESRD) without evidence of calcific uremic arteriolopathy. Abnormalities in small arteries or arterioles were present in 35% of amputation specimens and 55% of skin biopsies, and among these only thrombosis but not calcification was significantly more prevalent in skin biopsies. The prevalence of extravascular calcification did not differ. Vascular lesions were more common in skin biopsies from patients with high clinical suspicion of calcific uremic arteriolopathy (81%), significantly driven by increases in both calcification and thrombosis, compared to amputations (35%). The combination of medial calcification and thrombosis was six-fold more prevalent in high-suspicion skin biopsies than in amputation specimens. The location of affected vessels did not differ. In two autopsy cases, some but not all findings of involved skin were also present in uninvolved skin. Thus, histopathologic findings historically associated with calcific uremic arteriolopathy can also occur in viable tissue from unaffected patients with ESRD, calling into question the specificity of individual histologic findings for calcific uremic arteriolopathy. However, the combination of medial calcification and thrombosis was rare in unaffected patients and may provide a higher degree of specificity.

γδ T-cell function is inhibited in end-stage renal disease and impacted by latent tuberculosis infection.

Patients with end-stage renal disease (ESRD) are at elevated risk of acquiring infectious diseases, including tuberculosis (TB). Inflammation and uremia negatively impact immune function in this population, but specific pathways involved in TB immunity have not been identified. Although γδ T cells are known to contribute to protection from TB, their phenotype and function in patients with ESRD is relatively unknown. To determine this we recruited 20 patients with and 20 without ESRD (controls), with or without latent TB infection to assess γδ T cell frequency, surface phenotype, and cytokine production by flow cytometry in response to stimulation. γδ T cells derived from patients with ESRD exhibited significantly lower expression of CCR5, CXCR3, and CD26 compared to controls. Furthermore, patients with ESRD, particularly the group with latent TB infection, exhibited poor IFNγ, TNFα, and GMCSF responses to stimulation with either phosphoantigen HMB-PP, IL-12/IL-18, E. coli, or phorbol myristate acetate and ionomycin. Similar dysfunctional responses were observed in patients with active TB. Surprisingly, neither the γδ phenotype nor its function was associated with plasma markers of inflammation or microbial translocation. Thus, there is significant perturbation of the γδ T-cell population in patients with ESRD, particularly in those with latent TB infection.

Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach.

Gut microbiota is involved in the metabolism of uremic solutes. However, the precise influence of microbiota to the retention of uremic solutes in CKD is obscure. To clarify this, we compared adenine-induced renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles of plasma, feces, and urine using a capillary electrophoresis time-of-flight mass spectrometry-based approach. Mice with renal failure under germ-free conditions demonstrated significant changes in plasma metabolites. Among 183 detected solutes, plasma levels of 11 solutes, including major uremic toxins, were significantly lower in germ-free mice than in SPF mice with renal failure. These 11 solutes were considered microbiota-derived uremic solutes and included indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, γ-guanidinobutyrate, glutarate, 2-hydroxypentanoate, trimethylamine N-oxide, and phenaceturate. Metabolome profiling showed that these solutes were classified into three groups depending on their origins: completely derived from microbiota (indoxyl sulfate, p-cresyl sulfate), derived from both host and microbiota (dimethylglycine), and derived from both microbiota and dietary components (trimethylamine N-oxide). Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Microbiota-derived short-chain fatty acids and efficient amino acid utilization may have a renoprotective effect, and loss of these factors may exacerbate renal damage in germ-free mice with renal failure. Thus, microbiota contributes substantially to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression.

Identifying early pathogenic events during vascular calcification in uremic rats.

Vascular calcification in chronic kidney disease is a very complex process traditionally explained in multifactorial terms. Here we sought to clarify relevance of the diverse agents acting on vascular calcification in uremic rats and distinguish between initiating and complicating factors. After 5/6 nephrectomy, rats were fed a 1.2% phosphorus diet and analyzed at different time points. The earliest changes observed in the aortic wall were noticed 11 weeks after nephrectomy: increased Wnt inhibitor Dkk1 mRNA expression and tissue non-specific alkaline phosphatase (TNAP) expression and activity. First deposits of aortic calcium were observed after 12 weeks in areas of TNAP expression. Increased mRNA expressions of Runx2, BMP2, Pit1, Pit2, HOXA10, PHOSPHO1, Fetuin-A, ANKH, OPN, Klotho, cathepsin S, MMP2, and ENPP1 were also found after TNAP changes. Increased plasma concentrations of activin A and FGF23 were observed already at 11 weeks post-nephrectomy, while plasma PTH and phosphorus only increased after 20 weeks. Plasma pyrophosphate decreased after 20 weeks, but aortic pyrophosphate was not modified, nor was the aortic expression of MGP, Msx2, several carbonic anhydrases, osteoprotegerin, parathyroid hormone receptor-1, annexins II and V, and CD39. Thus, increased TNAP and Dkk1 expression in the aorta precedes initial calcium deposition, and this increase is only preceded by elevations in circulating FGF23 and activin A. The expression of other agents involved in vascular calcification only changes at later stages of chronic kidney disease, in a complex branching pattern that requires further clarification.

Paricalcitol and cinacalcet have disparate actions on parathyroid oxyphil cell content in patients with chronic kidney disease.

The parathyroid oxyphil cell content increases in patients with chronic kidney disease (CKD), and even more in patients treated with the calcimimetic cinacalcet and/or calcitriol for hyperparathyroidism. Oxyphil cells have significantly more calcium-sensing receptors than chief cells, suggesting that the calcium-sensing receptor and calcimimetics are involved in the transdifferentiation of a chief cell to an oxyphil cell type. Here, we compared the effect of the vitamin D analog paricalcitol (a less calcemic analog of calcitriol) and/or cinacalcet on the oxyphil cell content in patients with CKD to further investigate the genesis of these cells. Parathyroid tissue from four normal individuals and 27 patients with CKD who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Prior to parathyroidectomy, patients had received the following treatment: seven with no treatment, seven with cinacalcet only, eight with paricalcitol only, or cinacalcet plus paricalcitol in five. Oxyphilic areas of parathyroid tissue, reported as the mean percent of total tissue area per patient, were normal, 1.03; no treatment, 5.3; cinacalcet, 26.7 (significant vs. no treatment); paricalcitol, 6.9 (significant vs. cinacalcet; not significant vs. no treatment); and cinacalcet plus paricalcitol, 12.7. Cinacalcet treatment leads to a significant increase in parathyroid oxyphil cell content but paricalcitol does not, reinforcing a role for the calcium-sensing receptor activation in the transdifferentiation of chief-to-oxyphil cell type. Thus, two conventional treatments for hyperparathyroidism have disparate effects on parathyroid composition, and perhaps function. This finding is provocative and may be useful when evaluating future drugs for hyperparathyroidism.

Survival of Dialysis Patients with Restless Legs Syndrome: A 15-Year Follow-Up Study.

BACKGROUND: Restless legs syndrome, also known as Willis/Ekbom disease (RLS/WED), is a sleep-related, sensorimotor disorder with a high prevalence among end-stage renal disease (ESRD) patients undergoing haemodialysis (HD) (about 15-40%). Whether RLS/WED in uremic patients influences cardiovascular morbidity and mortality remains a matter of controversy. The aim of this study was to evaluate the relationship of RLS/WED and mortality in a population of chronically dialyzed patients. METHOD: In 1996, we studied 128 patients with ESRD undergoing HD; 47 subjects (36.7%) complained RLS/WED symptoms. Fifteen years later we evaluated the mortality of this population. No clinical follow-up examination of the uremic population was made. The Kaplan-Maier curves in dialysis patients with or without RLS/WED (control group matched for age) were constructed for all-cause mortality and compared using log-rank test. RESULTS: The Kaplan-Maier curves disclosed a lower mortality rate in the uremic patients with RLS/WED than in those without RLS/WED (p = 0.04). In our analysis, the mortality rate was not influenced by RLS/WED severity (p = 0.11) or gender (p = 0.15). No difference among the causes of death was found in the 2 groups. CONCLUSIONS: Our study suggests that mortality in ESRD patients is not influenced by concomitant RLS/WED. After a 15-year follow-up, survival rates in our cohort were significantly longer in uremic subjects with RLS/WED than in those without RLS/WED. Finally, we found no relationship between RLS/WED severity and mortality.

Acute and subacute oral toxicity of periodate salts in rats.

Periodate salts are being developed as potential replacements for perchlorate due to potential health hazards associated with exposure to perchlorate. The aim of this study was to investigate acute and subacute effects of periodate salts in rats. Acute oral toxicity of potassium and sodium periodate was determined using the Sequential Stage-Wise Probit method. The LD50 for potassium periodate was 732 (95% CI = 539-838, slope = 13.4) and 685 mg/kg (95% CI = 580-809, slope = 10.6) for females and males, respectively. The LD50 for sodium periodate was 318 (95% CI = 292-347, slope = 24.3) and 741 mg/kg (95% CI = 704-779, slope = 31.2) for females and males, respectively. In the subacute study, rats were administered sodium periodate at five doses (1/16 LD50 up to LD50) or distilled water for 14-days via oral gavage. Female rats in the 318 mg/kg-day group and male rats in the 185, 370, and 741 mg/kg-day groups exhibited moribundity, kidney toxicity, uremia, and a stress response. BMDL10s of 17.2 and 33.7 mg/kg-day were derived for females and males, respectively. Comparison with the NOAEL for perchlorate-induced thyroid toxicity in rats (0.009 mg/kg-day) suggests sodium periodate is less toxic than perchlorate on a subacute basis.

Efficacy and outcomes of continuous peritoneal dialysis versus daily intermittent hemodialysis in pediatric acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is associated with high patient morbidity and mortality. There is no consensus on the best RRT modality for pediatric AKI. METHODS: The efficacy and safety of continuous peritoneal dialysis (cPD) and daily intermittent hemodialysis (dHD) were compared in 136 children aged 1 month to 16 years requiring RRT for AKI. Mortality, risk factors and causes of death, 1-month and 3-month renal recovery rates, and technique-related complications were assessed. RESULTS: Uremia control and the rate of catheter-related complications were comparable in the groups. Thirty-day survival was 60.7 % (51 out of 84) with cPD and 36.5 % (19 out of 52) with dHD (p = 0.019). Although age <1 year, extended time lag from disease onset to RRT initiation, mechanical ventilation, and extended vasopressor dependence independently predicted death, adjusted mortality was higher with dHD relative to cPD (hazard ratio [HR] 1.75, 95%CI 1.18-2.84, p = 0.022). Almost all fatalities in the dHD group (94 %) occurred during or within an hour of a HD session. Renal function normalized in 27 % of survivors after 4 weeks and in 51 % after 3 months. The risk of permanent end-stage renal disease was increased in patients with an intrinsic renal cause of AKI (HR 2.72; 95 % CI 1.37-3.83; p = 0.029) and in those with delayed RRT initiation (HR 2.17; 95 % CI 123-2.93; p = 0.015), but did not differ between patients treated with dHD and cPD. CONCLUSIONS: Favorable patient survival with cPD compared with dHD in children treated for AKI was evident in this study.

Acute hemodynamic response and uremic toxin removal in conventional and extended hemodialysis and hemodiafiltration: a randomized crossover study.

BACKGROUND: Intensive hemodialysis (HD) may have significant benefits. Recently, the role of extended hemodiafiltration (HDF) has gained interest. The aim of this study was to evaluate the acute effects of extended HD and HDF on hemodynamic response and solute removal. STUDY DESIGN: Randomized crossover trial. SETTINGS & PARTICIPANTS: Stable patients with end-stage renal disease undergoing conventional HD. INTERVENTION: 13 patients randomly completed a single study of 4-hour HD (HD4), 4-hour HDF (HDF4), 8-hour HD (HD8), and 8-hour HDF (HDF8), with a 2-week interval between study sessions. Between study sessions, patients received routine conventional HD treatments. OUTCOMES: Acute hemodynamic effects and uremic toxin clearance. MEASUREMENTS: Blood pressure and heart rate, pulse wave analysis, cardiac output, and microvascular density by sublingual capillaroscopy, as well as relative blood volume and thermal variables, were measured. Clearance and removal of uremic toxins also were studied. RESULTS: Long treatments showed more stability of peripheral systolic blood pressure (change during HD4, -21.7±15.6 mm Hg; during HDF4, -23.3±20.8 mm Hg; during HD8, -6.7±15.2 mm Hg [P=0.04 vs. HD4; P=0.08 vs. HDF4]; and during HDF8, -0.5±14.4 mm Hg [P=0.004 vs. HD4; P=0.008 vs. HDF4]). A similar observation was found for peripheral diastolic and central blood pressures. Cardiac output remained more stable in extended sessions (change during HD4, -1.4±1.5 L/min; during HDF4, -1.6±1.0 L/min; during HD8, -0.4±0.9 L/min [P=0.02 vs. HDF4]; and during HDF8, -0.5±0.8 L/min [P=0.06 vs. HD4; P=0.03 vs. HDF4), in line with the decreased relative blood volume slope in long dialysis. No differences in microvascular density were found. Energy transfer rates were comparable (HD4, 13.3±4.7 W; HDF4, 16.2±5.6 W; HD8, 14.2±6.0 W; and HDF8, 14.5±4.3 W). Small-molecule and phosphate removal were superior during long treatments. ß2-Microglobulin and fibroblast growth factor 23 (FGF-23) reduction ratios were highest in HDF8. LIMITATIONS: Small sample size, only acute effects were studied. CONCLUSIONS: Treatment time, and not modality, was the determinant for the hemodynamic response. HDF significantly improved removal of middle molecules, with superior results in extended HDF.

Cardiorenal syndrome: the emerging role of protein-bound uremic toxins.

Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate-induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.

Quantification of plasma homocitrulline using hydrophilic interaction liquid chromatography (HILIC) coupled to tandem mass spectrometry.

Homocitrulline (HCit), an amino acid formed by the carbamylation of ε-amino groups of lysine residues, is considered a promising biomarker for monitoring diseases such as chronic renal failure and atherosclerosis. This paper describes a tandem mass spectrometric method for total, protein-bound and free HCit measurement in plasma samples. HCit was separated from other plasma components by hydrophilic interaction liquid chromatography. Detection was achieved by monitoring transitions of 190.1 > 127.1 and 190.1 > 173.1 for HCit, and 183.1 > 120.2 for d(7)-citrulline used as internal standard. This method allowed HCit quantification within 5.2 min and was precise (inter-assay CV < 5.85%), accurate (mean recoveries ranging from 97% to 106%), and exhibited a good linearity from 10 nmol/L to 1.6 µmol/L. Plasma samples from control and uremic mice (n = 10) were analyzed. In control mice, mean total plasma HCit concentration was 0.78 ± 0.12 µmol/mol amino acids, whereas it was increased 2.7-fold in uremic mice plasma, reaching 2.10 ± 0.50 µmol/mol amino acids (p < 0.001). In conclusion, this method exhibits good analytical performances and meets the criteria of sensitivity suitable for HCit concentration assessment in plasma samples.

Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1).

Untargeted metabolomics on the plasma and urine from wild-type and organic anion transporter-1 (Oat1/Slc22a6) knockout mice identified a number of physiologically important metabolites, including several not previously linked to Oat1-mediated transport. Several, such as indoxyl sulfate, derive from Phase II metabolism of enteric gut precursors and accumulate in chronic kidney disease (CKD). Other compounds included vitamins (pantothenic acid, 4-pyridoxic acid), urate, and metabolites in the tryptophan and nucleoside pathways. Three metabolites, indoxyl sulfate, kynurenine, and xanthurenic acid, were elevated in the plasma and interacted strongly and directly with Oat1 in vitro with IC50 of 18, 12, and 50 µM, respectively. A pharmacophore model based on several identified Oat1 substrates was used to screen the NCI database and candidate compounds interacting with Oat1 were validated in an in vitro assay. Together, the data suggest a complex, previously unidentified remote communication between the gut microbiome, Phase II metabolism in the liver, and elimination via Oats of the kidney, as well as indicating the importance of Oat1 in the handling of endogenous toxins associated with renal failure and uremia. The possibility that some of the compounds identified may be part of a larger remote sensing and signaling pathway is also discussed.

Protein-Bound Uremic Toxins and Immunity.

Protein-bound uremic toxins (PBUTs) are bioactive microbiota metabolites originated exclusively from protein fermentation of the bacterial community resident within the gut microbiota, whose composition and function is profoundly different in the chronic kidney disease (CKD) population. PBUTs accumulate in the later stages of CKD because they cannot be efficiently removed by conventional hemodialysis due to their high binding affinity for albumin, worsening their toxic effects, especially at the cardiovascular level. The accumulation of uremic toxins, along with oxidative stress products and pro-inflammatory cytokines, characterizes the uremic status of CKD patients which is increasingly associated to a state of immune dysfunction including both immune activation and immunodepression. Furthermore, the links between immune activation and cardiovascular disease (CVD), and between immunodepression and infection diseases, which are the two major complications of CKD, are becoming more and more evident. This review summarizes and discusses the current state of knowledge on the role of the main PBUTs, namely indoxyl sulfate and p-cresyl sulfate, as regulators of immune response in CKD, in order to understand whether a microbiota modulation may be useful in the management of its main complications, CVD, and infections. Summarizing the direct effects of PBUT on immune system we may conclude that PCS seemed to be associated to an immune deficiency status of CKD mainly related to the adaptative immune response, while IS seemed to reflect the activation of both innate and adaptative immune systems likely responsible of the CKD-associated inflammation. However, the exact role of IS and PCS on immunity modulation in physiological and pathological state still needs in-depth investigation, particularly in vivo studies.

The fractional excretion of urea in the differential diagnosis of prerenal failure and acute tubular necrosis in neonates.

BACKGROUND: Acute renal failure (ARF) in a newborn is a common problem. Fractional excretion of sodium (FENa) has been used to distinguish between the two main causes of ARF, prerenal failure and acute tubular necrosis (ATN). However, the clinical usefulness of FENa could be limited by furosemide diuretic that are commonly prescribed inARF patients. In contrast, urea is not reabsorbed significantly in the distal nephron, thus the fractional excretion of urea (FE UN) should not be affected by furosemide. OBJECTIVE: To test the hypothesis that FE UN is not effected by furosemide and useful in differentiating between prerenal failure and ATN. MATERIAL AND METHOD: Neonates admitted to the Department of Pediatrics, Thammasat University Hospital from August 2007-May 2009 were studies prospectively for ARF which is defined as urine output < 0.5 ml/kg/hr after the 1st day and serum creatinine > 1.5 mg/dl with normal maternal renal function. FENa and FEUN were performed on the initial time of diagnosis and were repeated on two consecutive days. RESULTS: Neonates with ARF were classified as prerenal failure (n=38) and ATN (n=5). The prerenal failure neonates were divided into two groups: those prerenal failure without furosemide (n=27), those prerenal failure with furosemide (n=11). The FENa at the initial time of diagnosis and the two consecutive days in prerenal failure neonates (0.33 +/- 0.57, 10.1 +/- 2.73, 0.8 +/- 1.32%, respectively) were lower than ATN neonates (4.74 +/- 6.12, 5.05 +/- 4.03, 3.98 +/- 2.47%, respectively) significantly. Both FENa and FE UN were no statistical difference between the two prerenal failure groups and ATN neonates. CONCLUSION: A FE Na in prerenal failure is significantly lower than ATN. A FE UN has no benefit in distinguishing between prerenal failure and ATN. Furosemide has no effect on both FENa and FE UN.

Blockage of the renin-angiotensin system attenuates mortality but not vascular calcification in uremic rats: sevelamer carbonate prevents vascular calcification.

BACKGROUND/AIMS: Hyperphosphatemia is associated with vascular calcification and increased cardiovascular morbidity and mortality. Angiotensin-converting enzyme inhibitors are beneficial in suppressing the progression of kidney and cardiovascular disease. The present studies explore the influence of enalapril and sevelamer carbonate on renal function, vascular calcification and mortality in long-term experimental uremia. METHODS: Normal and 5/6 nephrectomized rats were fed a high-phosphorus diet for 4 months and treated with enalapril or the combination of both enalapril and sevelamer carbonate. RESULTS: The rats treated with enalapril alone or both enalapril and sevelamer had less deterioration in renal function compared to uremic control as seen by lower serum creatinine (1.6, 1.6 vs. 2.1 mg/dl, respectively, p < 0.05) and higher creatinine clearance. They also exhibited attenuated mortality (23.5, 12.5 vs. 75%, respectively, p < 0.01) and inhibition of myocardial hypertrophy. Enalapril alone did not suppress secondary hyperparathyroidism or vascular calcification. Combination therapy with both enalapril and sevelamer carbonate ameliorated secondary hyperparathyroidism and vascular calcification (calcium content: 854 +/- 40 vs. 1,735 +/- 479 microg/g wet tissue) compared to uremic controls. CONCLUSION: In these experiments, animal mortality and myocardial hypertrophy were significantly reduced by both enalapril alone and enalapril in combination with sevelamer. In addition, sevelamer carbonate induced beneficial effects on renal dysfunction, secondary hyperparathyroidism and vascular calcification.

Comparison between fractional excretions of urea and sodium in children with acute kidney injury.

Fractional excretion of sodium (FENa) has been said to be the most sensitive index for differentiating prerenal failure (PRF) from intrinsic renal failure (IRF). However, there are several instances of high FENa (>2%) in cases of PRF and low FENa (<1%) in IRF patients. In contrast, the fractional excretion of urea nitrogen (FEUN) is primarily dependent on passive forces, and many confounding variables that affect FENa have little effect on FEUN, if any. To compare FEUN with FENa, pediatric patients with acute kidney injury (AKI) were prospectively evaluated by history, physical examination, and obtaining appropriate laboratory data during a 1-year interval. Diagnosis of PRF or IRF was made in each patient, and renal failure indices were compared between two groups using chi-square and t test, as appropriate. Probability value (P value) <0.05 was considered significant. Receiver operating characteristic (ROC) plots for FEUN and FENa were drawn to compare the discriminative power of each index. Forty-three patients were enrolled in the study. There were 27 patients in the PRF and 16 in the IRF group. FENa was 2+/-0.4 in PRF and 4.5+/- 1% in IRF patients (P<0.05), and low FENa (<1%) was only seen in 44.4% of PRF patients, which was not statistically different from those with IRF (P>0.05). FEUN was 23.6+/- 4.9% in PRF and 41.6+/-4.8% in IRF patients (P<0.05), and low FEUN (<35%) was seen in 77.8% of the PRF group (P<0.05). Cutoff values of 30% and 1.6% were reached for FEUN and FENa, respectively. In conclusion, FEUN <35% had higher sensitivity and specificity than FENa <1% for differentiation of PRF from IRF.

Molecular mechanisms of protein-bound uremic toxin-mediated cardiac, renal and vascular effects: underpinning intracellular targets for cardiorenal syndrome therapy.

Cardiorenal syndrome (CRS) remains a global health burden with a lack of definitive and effective treatment. Protein-bound uremic toxin (PBUT) overload has been identified as a non-traditional risk factor for cardiac, renal and vascular dysfunction due to significant albumin-binding properties, rendering these solutes non-dialyzable upon the state of irreversible kidney dysfunction. Although limited, experimental studies have investigated possible mechanisms in PBUT-mediated cardiac, renal and vascular effects. The ultimate aim is to identify relevant and efficacious targets that may translate beneficial outcomes in disease models and eventually in the clinic. This review will expand on detailed knowledge on mechanisms involved in detrimental effects of PBUT, specifically affecting the heart, kidney and vasculature, and explore potential effective intracellular targets to abolish their effects in CRS initiation and/or progression.