Nihil Chitalia

Vitamin D deficiency and endothelial dysfunction in non-dialysis chronic kidney disease patients

BACKGROUND Cardiovascular (CV) events are common in patients with chronic kidney disease (CKD) but inadequately explained by traditional risk factors. Vitamin D deficiency is highly prevalent in CKD and has been proposed to be a non-traditional risk factor, but its relationship with vascular function is unknown. METHODS AND RESULTS The aim of this study was to investigate the relationship between vitamin D levels and endothelial function in non-diabetes patients with mild to moderate CKD. Endothelial function was measured non-invasively using brachial artery flow mediated dilation (FMD). 25 hydroxy vitamin D levels were measured using electrochemiluminescence immunoassay. In 50 CKD patients (age 56±11 years, BMI 25±4kg/m(2), 46% females, 14% smokers, 86% hypertensives, 52% with dyslipidaemia) the mean vitamin D level was 53±33nmol/L (21±13ng/L). The mean FMD was 3.8±2.4%. Decreasing 25 hydroxy vitamin D levels were associated with decreasing FMD [r=0.44, p=0.001]. In multivariate analysis the association remained independent after adjustment with traditional risk factors (adjusted beta 0.451; t=3.46; p<0.002). Patients with low vitamin D (≤37.5nmol/L) demonstrated low FMD compared to patients with vitamin D values >37.5nmol/L (4.4±2.5% vs. 2.5±1.6%; p=0.007); however the traditional risk factors were similar between the two groups. CONCLUSION This is the first demonstration of an association of vitamin D deficiency with abnormal vascular endothelial function in non-dialysis CKD patients. Further studies with intervention and exploration of the mechanism are needed to establish a cause effect relationship.

Impact of vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients.

Background Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease (CKD). We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function, endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [25(OH)D] is unknown, which this study investigated. Methods We assessed non-diabetic patients with CKD stage 3/4, age 17–80 years and serum 25(OH)D <75 nmol/L. Brachial artery Flow Mediated Dilation (FMD), Pulse Wave Velocity (PWV), Augmentation Index (AI) and circulating blood biomarkers were evaluated at baseline and at 16 weeks. Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks. Results Clinical characteristics of 26 patients were: age 50±14 (mean±1SD) years, eGFR 41±11 ml/min/1.73 m2, males 73%, dyslipidaemia 36%, smokers 23% and hypertensives 87%. At 16-week serum 25(OH)D and calcium increased (43±16 to 84±29 nmol/L, p<0.001 and 2.37±0.09 to 2.42±0.09 mmol/L; p = 0.004, respectively) and parathyroid hormone decreased (10.8±8.6 to 7.4±4.4; p = 0.001). FMD improved from 3.1±3.3% to 6.1±3.7%, p = 0.001. Endothelial biomarker concentrations decreased: E-Selectin from 5666±2123 to 5256±2058 pg/mL; p = 0.032, ICAM-1, 3.45±0.01 to 3.10±1.04 ng/mL; p = 0.038 and VCAM-1, 54±33 to 42±33 ng/mL; p = 0.006. eGFR, BP, PWV, AI, hsCRP, von Willebrand factor and Fibroblast Growth Factor-23, remained unchanged. Conclusion This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness, serum calcium or FGF-23. Trial Registration ClinicalTrials.gov NCT02005718

Insulin Resistance, Inflammation, and Vascular Disease in Nondiabetic Predialysis Chronic Kidney Disease Patients

Chronic kidney disease (CKD) is associated with high cardiovascular morbidity and mortality, which is not fully explained by traditional risk factors; hence, the interest in nontraditional risk factors such as inflammation and insulin resistance (IR). Though IR is shown in nondiabetic CKD, its association with vascular disease and inflammation in this population is unknown, and is what this study aims to investigate.

Left ventricular hypertrophy and endothelial dysfunction in chronic kidney disease

UNLABELLED Aim Mortality, predominantly due to cardiovascular events, is high in patients with chronic kidney disease (CKD) and left ventricular hypertrophy (LVH) is a strong risk factor. Vascular endothelial dysfunction (ED) is common in CKD, but its potential contribution to LVH in non-dialysis CKD is unknown. This study investigated the association of ED with LVH in non-dialysis CKD patients. METHODS AND RESULTS We studied 30 CKD patients (17 pre-dialysis and 13 renal transplant recipients) and 29 age-gender-matched controls. In both groups, high-sensitivity C-reactive protein (hsCRP) levels, systemic ED (brachial artery flow-mediated dilatation, FMD), and LVH using two-dimensional echocardiography were measured. LV mass index (LVMI) was calculated using Penn formula and indexed by height. CKD patients had higher CRP levels (3.9 ± 2.8 vs. 1.0 ± 0.7 mg/L; P < 0.001), reduced FMD (3.2 ± 2.1 vs. 6.1 ± 1.9%; P < 0.001), and increased LVMI (146.1 ± 40.2 vs. 105.3 ± 26.2 g/m; P < 0.001), compared with controls. In CKD patients, LVMI increased with decreasing FMD (r = -0.371; P = 0.043) and FMD decreased with increasing CRP (r = -0.741; P < 0.001). Patients with low FMD <2.3% had higher CRP and LVMI (161.9 ± 48.9 vs. 130.4 ± 20.7 g/m; P = 0.033), compared with CKD patients with FMD ≥2.3%. There was no significant difference in age, blood pressure, cholesterol, FMD, and LVMI between pre-dialysis and post-renal transplant CKD patients. In multivariate regression, the relationship between LVMI and FMD remained significant after adjusting for age, diabetes, and smoking (adjacent beta = -0.396; P = 0.004). CONCLUSION This pilot study demonstrates for the first time a relationship of ED with LVH in non-dialysis CKD patients; suggesting but not proving a cause-effect relationship.

Neointimal Hyperplasia and Calcification in Medium Sized Arteries in Adult Patients with Chronic Kidney Disease

The nature of arterial changes resulting in cardiovascular events and dialysis vascular access failures in adult predialysis patients is not well known. This study examined intimal changes, calcium deposition, and consequent stiffness in brachial and radial arteries of adult CKD patients. Ten brachial‐artery and seven radial‐artery specimens were obtained during fistula creation from nine predialysis and eight dialysis‐dependent, nondiabetic patients; and age‐gender matched controls undergoing coronary bypass grafts (6 radial) or kidney donation (6 renal). Arterial stiffness was measured at baseline. Vessel histology, morphometric analysis of intima‐media, and direct quantification of calcium load was performed using standard techniques. Both predialysis and dialysis patients demonstrated significant arterial intimal hyperplasia with intima:media ratio higher than controls (0.13 ± 0.12 vs. 0.02 ± 0.05, p = 0.01). Calcium deposition was demonstrated on histology and the calcium content in patients was higher than controls (34.68 ± 26.86 vs. 10.95 ± 9.18 μg/μg, p = 0.003). The blood vessel calcium content correlated with arterial stiffness (r = 0.64, p = 0.018). This study for the first time describes, and suggests mechanistic linkage between, intimal hyperplasia, pathological calcium deposition, and increased functional arterial stiffness in dialysis and predialysis patients. Our research could serve as a unique window into the in vivo status of the uremic vasculature impacting fistula maturation and cardiovascular disease.

Aldosterone-producing adrenal adenoma and idiopathic intracranial hypertension—a pathogenetic link for aldosterone?

A 49-year-old Caucasian male with poorly controlled hypertension was admitted to St George’s Hospital in 1998 with a 6-week history of headaches and visual obscuration. He had an episode of left ventricular failure 8 months previously. A subsequent coronary and renal angiogram were normal. Hypertension was diagnosed 5 years previously and he was on treatment with amlodipine 10 mg od, methyldopa 250 mg tds, doxazosin 2 mg qds, labetalol 200 mg bd and furosemide 40 mg bd. His blood pressure (BP) was 160/90 mmHg on admission. Visual acuity was reduced in both eyes with bilateral papilloedema worse on the left than on the right. Magnetic resonance imaging (MRI) of his brain was normal. Diagnostic lumbar puncture (LP) revealed a high cerebrospinal fluid (CSF) opening pressure at 270 mmH2O (reference range 60–220 mmH2O). CSF of 4.5 ml was drained with a fall in CSF pressure to 165 mmH2O along with subjective improvement in headaches. On the basis of a normal MRI brain, bilateral papilloedema and high CSF pressure, he was diagnosed with idiopathic intracranial hypertension (IIH). His vision, however, did not improve and he underwent an optic nerve sheath fenestration to relieve the pressure on the left optic nerve. The patient was referred to the Blood Pressure Unit at St George’s Hospital in January 2003 with resistant hypertension with a BP of 210/100 mmHg. Initial investigations showed serum Na+ 139 mmol/l, serum K+ 3.5 mmol/l and bicarbonate 29 mmol/l. His plasma aldosterone concentration was 1476 pmol/l (normal range of 100–600 pmol/l) and his plasma renin activity (PRA) was suppressed at 0.1 ng/ml/h (normal upright range of 0.5–4.5 ng/ml/h) giving a plasma aldosterone concentration to PRA [aldosterone to renin (ARR)] ratio of 14760. Urinary catecholamines were normal. A computerized tomography (CT) scan of his …

Echocardiographic abnormalities in patients on kidney transplant waiting list.

BACKGROUND Echocardiographic abnormalities are well described in chronic kidney disease (CKD), and associated with increased cardiovascular events (CVEs) and mortality. Little is known regarding progression of these abnormalities in patients awaiting kidney transplantation. METHODS We assessed the progression of echocardiographic variables in patients awaiting kidney transplantation and determined predictors of CVEs and mortality. The study included all patients awaiting kidney transplantation between 2004 and 2010 with repeat echocardiograms at least 1 year apart and at least 1 year after transplantation. RESULTS We assessed 79 patients (57% male, mean age 55 ± 11 years; 27% with diabetes). Sixty-three patients remained on waiting list, and 16 had kidney transplants. Two deaths and 2 CVEs occurred in patients awaiting kidney transplantation. Repeat echocardiograms (31 ± 19 months from baseline) on patients who remained on waiting list showed significant increases in left ventricular mass index (LVMI) (55.3 ± 17.8 vs. 60.5 ± 21.9 g/m2.7, p=0.02) and in left atrium (LA) diameter (3.8 ± 0.6 vs. 4.1 ± 0.8 cm, p=0.02). There were no significant changes in LV fractional shortening (FS) or LV end-systolic and end-diastolic dimensions. Left atrium diameter (p=0.005), systolic dysfunction (p=0.007) and LVMI (p=0.01) were independent predictors of CVEs and mortality. CONCLUSIONS Time on kidney transplant waiting list is associated with progressive increases in LA diameter and LVM, which are markers of adverse outcome.

Killer cell immunoglobulin receptor profile on CD4(+) CD28(-) T cells and their pathogenic role in non-dialysis-dependent and dialysis-dependent chronic kidney disease patients.

There is a progressive increase in cardiovascular disease with declining renal function, unexplained by traditional risk factors. A CD4+ T‐cell subpopulation (CD4+ CD28−), activated by human heat‐shock protein 60 (hHSP 60), expands in patients with acute coronary syndrome and is associated with vascular damage. These cells exhibit cytotoxicity via expression of activating killer cell‐immunoglobulin‐like receptor KIR2DS2, mainly in the absence of inhibitory KIR2DL3. We investigated expansion of these cells and the pathogenic role of the KIR in non‐dialysis‐dependent chronic kidney disease (NDD‐CKD) and end‐stage haemodialysis‐dependent renal disease (HD‐ESRD) patients. CD4+ CD28− cells were present in 27% of the NDD‐CKD and HD‐ESRD patients (8–11% and 10–11% of CD4+ compartment, respectively). CD4+ CD28− cells were phenotyped for KIR and DAP12 expression. Cytotoxicity was assessed by perforin and pro‐inflammatory function by interferon‐γ expression on CD4+ CD28− clones (NDD‐CKD n = 97, HD‐ESRD n = 262). Thirty‐four per cent of the CD4+ CD28− cells from NDD‐CKD expressed KIR2DS2 compared with 56% in HD‐ESRD patients (P = 0·03). However, 20% of clones expressed KIR2DL3 in NDD‐CKD compared with 7% in HD‐ESRD patients (P = 0·004). DAP12 expression in CD28− 2DS2+ clones was more prevalent in HD‐ESRD than NDD‐CKD (92% versus 60%; P < 0·001). Only 2DS2+ 2DL3− DAP12+ clones were cytotoxic in response to hHSP 60. CD4+ CD28− cells exhibited increased KIR2DS2, reduced KIR2DL3 and increased DAP12 expression in HD‐ESRD compared with NDD‐CKD patients. These findings suggest a gradual loss of expression, functionality and protective role of inhibitory KIR2DL3 as well as increased cytotoxic potential of CD4+ C28− cells with progressive renal impairment. Clonal expansion of these T cells may contribute to heightened cardiovascular events in HD‐ESRD.

Pulse Pressure Relationships with Demographics and Kidney Function in Ashanti, Ghana

Introduction Hypertension, particularly pulse pressure [PP] is a major risk factor for end-stage renal disease. However, the effect of individual components of hypertension namely PP, systolic [SBP] and diastolic blood pressure [DBP] on kidney function, in the general African population is unknown. Methods Data were collected on 944 participants [aged 40-75 y], living in villages in the area around the city of Kumasi, Ghana, on demographics, medications, height, weight, BP and 24-hour creatinine clearance (CrCl). Results The demographic and clinical characteristics were: age 55(11) [mean (SD)] years, females 62%, rural village-dwellers 52%, diabetes 1·5%, BMI 21(4) kg/m2, 24-hourCrCl as a measure of glomerular filtration rate (GFR) 84(23) ml/min/1.73 m2. 29% had BP >140/90 mmHg; SBP and DBP were 125/74(26/14) mmHg, PP was 51(17) mmHg. PP increased with age by 0.55(95% CI: 0.46,0.64) mmHg/year. PP was higher (53(17) v 49(15) mmHg; p < 0.001) in the semiurban participants. GFR decreased both with increasing PP [-0.19 (-0.27,-0.10 ml/min/1.73 m2/mmHg; p < 0.001] and SBP [-0.09 (-0.14,-0.03) ml/min/1.73 m2/mmHg; p < 0.001] but there was no significant relationship with DBP [-0.04 (-0.15,0.06)]. After adjusting for SBP, the relationship between GFR and PP became steeper [-0.31 (-0.50,-0.12) ml/min/1.73 m2/mmHg; p < 0.001]. Using multivariate regression analysis that included PP, age, gender, BMI, only increasing age [-0.75 (-0.88,-0.62)] and decreasing BMI [0.49 (0.16,0.81)] were associated with decreased kidney function. Conclusions In this homogeneous West-African population, PP increased with age and had a steeper relationship with declining kidney function than SBP or DBP.