Molecular Mechanisms of Peritoneal Dialysis–Induced Microvascular Vasodilation

Peritoneal dialysis (PD) solutions dilate microvessels by undefined mechanisms. This vasodilation directly affects ultrafiltration and solute exchange during a PD dwell and is thought to account for the variable mass transfer area coefficient for small solutes during a glucose-based hypertonic dwell. We hypothesized that PD-mediated vasodilation occurs by endothelium-dependent mechanisms that involve endothelium energy-dependent K+ channels (KATP), adenosine A1 receptor activation, and NO release. We used intravital videomicroscopy to study 3 levels of microvessels (A1 inflow arterioles about 100 μm diameter to pre-capillary A3 arterioles 10 – 15 μm diameter) in the terminal ileum of anesthetized rats under control conditions in vivo in a tissue bath. Ileum was bathed with hypertonic mannitol or 2.5% glucose-based PD solution (Delflex: Fresenius Medical Care North America, Waltham, MA, U.S.A.) with or without topical application of individual or combined specific inhibitors of the endotheliumdependent dilation pathways: NO (L-NMMA), prostaglandin I2 (mefenamic acid), endothelium hyperpolarizing factor (glibenclamide), and adenosine A1 receptor antagonist (DPCPX). The mannitol and PD solutions induced rapid and sustained peritoneal vasodilation whose magnitude depended on microvascular level and osmotic solute. Combined inhibition of endothelium-dependent dilation pathways completely abolished the mannitolinduced hyperosmolality-mediated dilation at all microvascular levels, but selectively eliminated the PD solution–mediated A3 dilation. The KATP and adenosine receptor antagonists, individually or combined, remarkably attenuated dilation in the smaller pre-capillary arterioles; NO inhibition, alone or combined with KATP and adenosine receptor antagonists, eliminated the PD solution–induced dilation. The cyclooxygenase pathway is not involved in PD-induced dilation. Solutions for PD dilate the visceral peritoneal microvasculature by endothelium-dependent mechanisms, primarily the NO pathway. Adenosine receptor–activated NO release and KATP channelmediated endothelium hyperpolarization significantly contribute to vasodilation in the smaller peritoneal pre-capillary arterioles.Qatar National Research Fund NPRP 09-268-3-06

Demographic data and hemodialysis population dynamics in Qatar: A five year survey

Hemodialysis was initiated in Qatar in 1981, since then the hemodialysis population has been expanding rapidly. This report describes the demographics and outcome of our hemo-dialysis patients during a five years study period. Data of all the patients on regular hemodialysis from January 1 st , 2002 to December 31 st , 2006 were included in this study was collected from the medical records and entered into an especially designed questionnaire. The prevalence of end stage kidney disease in Qatar is 624 patients per million populations with an incidence of 202 patients per million populations per year. Currently, 278 patients are on hemodialysis, 65% of them are Qatari, males represent 51%, whereas 44.6% are between 65-74 years of age. Diabetic nephropathy is the commonest cause of end stage kidney disease (48%), followed by primary glomerulonephritis and hypertensive glomerulopathy. Arteriovenous fistula was the vascular access in 57% of patients. The incidence of Hepatitis B, C and Human immunodeficiency virus had been stable throughhout the study period though our hemodialysis population had increased by 1.5 fold. The first and five years survival rates of our patients were 84 and 53% respectively. Qatar has one of the highest rates of dialysis patients with a good long-term survival report. Peritoneal dialysis remained to be the key solution for the rapidly expanding patients′ pool. Maintenance of national registry of dialysis patients and improving our organ transplant program is an essential goal

Mutational analysis of AGXT gene in Libyan children with primary hyperoxaluria type 1 at Tripoli Children Hospital

Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism. It results from genetic mutation of the AGXT gene. The study objective was to verify the clinical and epidemiological patterns of PH1 in Libyan children at Tripoli Children Hospital confirmed by AGXT gene mutation. A descriptive case series study of 53 children with PH1 diagnosed between 1994 and 2015 was carried out in the Nephrology Unit at Tripoli Children Hospital. Diagnosis of PH1 was based on the clinical presentation (renal stones or nephrocalcinosis), positive family history of PH1, and high 24 h urinary oxalate. Sampling for AGXT gene mutation was collected from April 2012 to December. 2015. Among the 53 children included, males composed of 62.3% of patients. Their age at presentation ranged between two months and 20 years with a mean age of 55.4 ± 48 months. The parents of 81.1% of these patients had positive consanguinity. Forty (75.5%) patients were from South West (mountain area), and 16 (40%) of them were from Yefrin. The most common mutation found in this study was c.731T>C (p.lle244thr) seen in 32 (71%) of children, and interestingly, among these patients, 87.1% were homozygous in gene typing, 86.2% had positive history of consanguinity, 71.4% were from South West (mountain area), 96.6% had family history of PH1, and 20% presented with impaired renal function. The patients with this mutation were younger at presentation than that with other genes, and it was more prevalent among boys (61.3%). Thus, the most common gene mutation found in Libyan children with PH1 was c.731T>C (p.lle244thr) and this is more likely due to the strong genetic pooling caused by the high consanguinity rate which requires an extensive genetic counseling

Hyperosmolality-Mediated Peritoneal Microvascular Vasodilation Is Linked to Aquaporin Function

Glucose-based peritoneal dialysis (PD) solutions dilate the parietal and visceral peritoneal microvasculature by endothelium-dependent mechanisms that primarily involve hyperosmolality. This PD-mediated dilation occurs by active intracellular glucose uptake and adenosine A1 receptor activation, and by hyperosmolality-stimulated glibenclamide-sensitive potassium channels. Both pathways invoke NO as a second messenger for vasodilation. We hypothesized that during crystalloid-induced osmosis, the osmotic water flux through the transendothelial water-exclusive aquaporin 1 (AQP1) channels is the primary mechanism whereby the endothelium is being stimulated to instigate hyperosmolality-driven vasodilation. Four microvascular levels (diameters in the range 6 – 100 μm) were visualized by intravital videomicroscopy of the terminal ileum in anesthetized rats. Microvascular diameters and flow were measured after topical exposure to a 5% hypertonic mannitol or 2.5% glucose-based PD solution, at baseline and after brief tissue pre-treatment (with 0.1% glutaraldehyde for 10 seconds) or after combined tissue pre-treatment and pharmacologic blockade of AQP1 with HgCl2 (100 μmol/L). Vascular endothelial integrity was verified by the response to acetylcholine (10–4 mol/L) and sodium nitroprusside (10–4 mol/L). The hyperosmolar solutions both caused rapid and sustained vasodilation at all microvascular levels, which was not altered by tissue pre-treatment. Inhibition of AQP1 completely abolished the mannitolinduced vasodilation and markedly attenuated the PD fluid–mediated vasodilation. Neither glutaraldehyde pre-treatment nor HgCl2 affected tissue integrity or endothelial cell function. We conclude that the peritoneal microvascular vasodilation caused by hyperosmolar PD fluid is instigated by the osmotic water flux through AQP1. Clinical PD solutions have components other than hyperosmolality that can induce endothelium-dependent peritoneal microvascular vasodilation independent of the AQP1-mediated osmosis.research grant NPRP 09-268-3-066, funded by the Qatar National Research Fun

Intervention using vitamin D for elevated urinary albumin in type 2 diabetes mellitus (IDEAL-2 Study): study protocol for a randomised controlled trial

Abstract Background The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. T2DM is associated with serious macro- and microvascular complications. In particular, diabetic kidney disease (DKD), which begins with excessive urinary albumin excretion, has a significant impact on affected individuals and is costly to healthcare services. Inhibition of the renin–angiotensin–aldosterone system (RAAS) with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) significantly reduces albuminuria in diabetes, but this effect is not observed in all those treated. Active vitamin D analogues have been observed to be reno-protective through inhibition of RAAS in animal and human studies. Therefore, it can be hypothesised that an active vitamin D analogue will have an additional benefit to ACEI/ARB treatment for albuminuria reduction in DKD. Methods The planned study is an ongoing non-blinded randomised controlled parallel-group trial examining the impact, in individuals with T2DM, of the addition of bioactive vitamin D (calcitriol) to RAAS inhibition treatment using ACI or ARB on urinary albumin excretion over a period of 26 weeks. The primary outcome measure is the urinary albumin creatinine ratio. It is planned for the study to recruit 320 participants. Other outcome measures of interest include 24-h urine albumin (24 h UA) excretion, estimated glomerular filtration rate (eGFR), blood pressure and quality of life. Safety will be assessed throughout. Discussion If the addition of calcitriol to RAAS inhibition with ACEI or ARB safely results in a significant reduction in albuminuria, the study adds to the body of evidence supporting a role for vitamin D in reno-protection, will inform clinical practice and could result in significant reduction of healthcare costs associated with DKD. Trial registration ISRCTN, ISRCTN86739609. Registered on 7 June 2017. ClinicalTrials.gov, NCT03216564. Registered on 13 July 2017

Additional file 1: of Intervention using vitamin D for elevated urinary albumin in type 2 diabetes mellitus (IDEAL-2 Study): study protocol for a randomised controlled trial

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Peritoneal dialysis, an expanding mode of renal replacement therapy in Qatar

Qatar is one of the gulf countries with a current estimated population of 1.4 million. Diabetes mellitus, hypertension and chronic kidney diseases are major emerging epidemics, with an incidence of end-stage kidney disease (ESKD) of 202 patients per million population per year. Peritoneal dialysis (PD) was initiated in Qatar in 1997 with a rapid expansion in the number of patients. The study included all patients performing PD in Qatar, during the period from 1 January 2003 to 31 December 2007. Retrospective analysis of data included the records of 241 patients in terms of their demography, treatment, complications, and survival. During the study period, PD patients formed 23% of all the dialysis population in Qatar, with a mean annual expansion rate of 12%. Diabetic nephropathy was the commonest cause of ESKD seen in 43% of PD patients. All age groups were included in our program, with a mean age of 53 ± 13 years. Males represented 74%. Continuous ambulatory peritoneal dialysis remained the initial mode of PD, with significant numbers being changed to automated PD over the years. The 1- and 5-year survival rates were 91% and 26%, respectively, with cardiac causes being responsible for 86% of mortality. The rate of peritonitis was 0.24 ± 0.1 episodes per patient years, and technique survival at 1 and 5 year was 84% and 32%, respectively. We conclude that the components of the PD program in Qatar are comparable to that in other countries with a good outcome

Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection

Fractalkine (Fk) is a structurally unusual member of the chemokine family. To determine its role in vivo, we generated mice with a targeted disruption of CX(3)CR1, the receptor for Fk. CX(3)CR1(–/–) mice were phenotypically indistinguishable from wild-type mice in a pathogen-free environment. In response to antibody-induced glomerulonephritis, CX(3)CR1(–/–) and CX(3)CR1(+/+) mice had similar levels of proteinuria and injury. CX(3)CR1(–/–) and CX(3)CR1(+/+) mice also developed similar levels of disease in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. We performed heterotopic MHC class I/II cardiac transplants from BALB/c mice into C57BL/6 mice. In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX(3)CR1(–/–) and CX(3)CR1(+/+) recipient mice. However, in the presence of subtherapeutic levels of CsA, graft survival time was significantly increased in the CX(3)CR1(–/–) mice. Characterization of cells infiltrating the grafts revealed a selective reduction in natural killer cells in the CX(3)CR1(–/–) recipients in the absence of CsA and a reduction in macrophages, natural killer cells, and other leukocytes in the presence of CsA. We conclude that Fk plays an important role in graft rejection. The development of CX(3)CR1 antagonists may allow reductions in the doses of immunosuppressive drugs used in transplantation