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.

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.

Determinants of vitamin D status in long-term renal transplant patients.

In this study, we explored the determinants of vitamin D status in a large cohort of stable, Long-term renal transplant (RTx) patients. Serum 25(OH)D concentrations, and bone biochemistry parameters, were retrospectively analyzed from 266 RTx patients (>10 yr post-engraftment) presenting to clinic over the course of a year. Forty-five percent of the cohort were vitamin D deficient (<37.5 nM), 38% insufficient (37.5 75-nM), and 17% sufficient (>75 nM). Serum 25(OH)D concentrations were higher in patients presenting in summer (p<0.001) and in more active patients (p<0.05). RTx patients with non-melanoma skin cancer (NMSC) (n=45) had higher 25(OH)D concentrations than patients without NMSC (n=221; p<0.05) despite these patients being older, having worse eGFR, transplanted for longer, and less active physically (p<0.05). Lower 25(OH)D concentrations were associated with higher PTH concentrations (p<0.05) which, in the setting of widespread hypovitaminosis, suggests that secondary hyperparathyroidism was common in this cohort. In conclusion, season and activity status are important determinants of vitamin D status. We report, for the first time, that NMSC is associated with higher 25(OH)D, probably through increased UV radiation exposure. Long-term RTx patients may benefit from oral vitamin D supplementation, but this requires a randomized controlled trial to confirm.

Impact of vitamin D on cardiac structure and function in chronic kidney disease patients with hypovitaminosis D: a randomized controlled trial and meta-analysis.

AIMS: Vitamin D deficiency is associated with cardiovascular events in chronic kidney disease (CKD) yet the impact of supplementation is controversial. Previous active vitamin D supplementation studies did not show improvement in cardiac structure or function but the effect of native vitamin D supplementation in CKD patients with low vitamin D levels is unknown. We have addressed this question via both a randomized double-blind prospective study and a meta-analysis of three randomized placebo-controlled studies. METHODS AND RESULTS: We conducted a randomized double-blind, placebo-controlled trial of vitamin D supplementation in stable, non-diabetic, CKD three to four patients with circulating vitamin D <75nmol/L, who were receiving treatment with ACEi or ARB and had high-normal left ventricular (LV) mass. Patients were randomized to receive six directly observed doses of 100 000 IU cholecalciferol (n = 25) or matched placebo (n = 23). The primary endpoint was changed in LV mass index (LVMI) over 52 weeks, as assessed by cardiac magnetic resonance imaging. Secondary endpoints included changes in LV ejection fraction (LVEF); LV and right ventricular volumes and left and right atrial area. Vitamin D concentration increased with the administration of cholecalciferol. The change in LVMI with cholecalciferol [median (inter-quartile range), -0.25 g (-7.20 to 5.30)] was no different from placebo [-4.30 g (9.70 to 2.60)]. There was no difference in changes of LVEF; LV and right ventricular volumes and left and right atrial area. The meta-analysis of three 52-week, randomized placebo-controlled studies using active/native vitamin D supplementation showed no differences in LVMI measurements. CONCLUSION: Vitamin D supplementation does not have beneficial effects on LV mass in CKD patients.

Serum adiponectin and cardiovascular risk in chronic kidney disease and kidney transplantation.

BACKGROUND: Serum adiponectin is inversely linked to obesity, impaired glucose homeostasis, dyslipidemia and hypertension and has been suggested as a possible marker of cardiovascular (CV) disease in the general population. However, its role in chronic kidney disease and following renal transplantation is not well established. METHODS: This study examined the relationship of adiponectin with CV risk factors and kidney function in patients with predialysis chronic kidney disease (CKD) (n=33) and those who had undergone a renal transplantation (n=43). Serum adiponectin was measured using ELISA. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) study formula. Associations of adiponectin with clinical and laboratory parameters were tested. RESULTS: Mean age of the population was 37 +/- 11 years, 83% were men, 18% had diabetes and mean GFR was 48 +/- 29 ml/min per 1.73 m2. Adiponectin levels inversely related with eGFR (p=0.021), body mass index (BMI) (p=0.024), waist circumference (p=0.018) and hemoglobin (p=0.004), and directly related with high-sensitivity C-reactive protein (hsCRP) (p=0.019). It did not correlate with blood pressure, lipids, fasting glucose or smoking. On multivariate analysis, eGFR (beta=-0.360, p=0.002) and BMI (beta=-0.346, p=0.003) were independent determinants of adiponectin, adjusted for age, sex, lipids, diabetes, hypertension and transplant status. Renal transplant patients had lower CV risk, however adiponectin was similar to CKD patients (22 +/- 17 vs. 23 +/- 21; p=0.8). Adiponectin was inversely related to eGFR (p=0.003). CONCLUSION: This is the first study showing that serum adiponectin is a poor predictor of cardiovascular risk in both the CKD and renal transplant population. Serum adiponectin levels are influenced by renal function. Adiponectin levels increased with decreasing kidney function in CKD renal transplant recipients. Despite better CV risk profile, transplant patients had similar adiponectin levels to those of CKD patients. We conclude that adiponectin levels do not reflect the high CV risk in CKD.

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.

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.

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.

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.

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.

Metabolic syndrome in chronic kidney disease and renal transplant patients in North India.

AIM: The cluster of biochemical and clinical abnormalities known as metabolic syndrome (MS) has become a public health problem even in developing countries. Previous studies have shown a graded relationship between MS components and worsening renal function in the general population. The prevalence of MS in non-dialysis-dependent CKD (NDD-CKD) and kidney transplant recipients in the North Indian population is unknown. METHODS: We studied all patients with stable CKD and with renal transplantation attending the nephrology clinic in a large centre in North India over an eight-week period. All transplant patients had stable graft function for 3 months prior to recruitment. MS was defined according to the International Diabetes Federation (IDF) 2007 guidelines. A total of 252 (155 NDD-CKD and 97 renal transplant recipients) patients were studied. RESULTS: MS was present in 86 (34%) patients. The prevalence of MS was similar in NDD-CKD and transplant patients [60 (39%) vs. 26 (27%), P = 0.052]. Patients with MS were older than those without MS (48 ± 12 years-old vs. 40 ± 14 years-old, P < 0.001) and MS was more common in women than in men (59% vs. 26%, P < 0.001). Female gender was an independent risk factor for MS in this population [adjusted OR 5.25 (95% CI: 2.74-10.06)]. With advancing CKD, the prevalence of MS decreased in the NDD-CKD patients. Impaired glucose tolerance and hypertriglyceridemia were independent predictors of MS. Hypertension was not a predictor of MS in NDD-CKD. In transplant recipients, hypertriglyceridemia, hypertension and low HDL cholesterol predicted the risk for MS. CONCLUSION: MS is common in CKD and renal transplant patients in North India. The risk of MS decreases with declining eGFR in CKD patients. Female gender and hypertriglyceridemia independently predict the risk of MS in both NDD-CKD and transplant recipients.

Insulin resistance, inflammation, and vascular disease in nondiabetic predialysis chronic kidney disease patients.

BACKGROUND: 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. HYPOTHESIS: IR and inflammation are related to vascular disease in nondiabetic predialysis CKD patients. METHODS: We studied carotid-artery intima-media thickness (IMT) and endothelial function (brachial artery flow mediated dilation [FMD]) in 35 nondiabetic predialysis patients with stage 3-5 CKD and 35 age- and gender-matched controls. Insulin resistance was measured using the homeostasis model assessment for insulin resistance score (HOMA-IR), inflammation by high-sensitivity CRP (hsCRP), and their relationship with FMD and IMT. RESULTS: Patients with CKD showed reduced FMD (3.34 ± 2.14% vs. 5.27 ± 1.78%, P<0.001) and increased IMT (0.78 ± 0.22 mm vs. 0.64 ± 0.16 mm, P = 0.003) compared with controls. The CKD patients had a higher HOMA-IR (2.20 ± 1.08 vs. 1.13 ± 0.64, P<0.001) and hsCRP (3.25 ± 5.47 mg/L vs. 1.10 ± 1.85 mg/L [median ± interquartile range], P = 0.02). In the study population, HOMA-IR was directly related to hsCRP. After adjusting for traditional risk factors, high HOMA-IR and hsCRP were significantly related to decreased FMD (adjusted ß = -0.44, 95% confidence interval [CI]: -1.55 to -0.08, P = 0.003 and adjusted ß = -0.51, 95% CI: -0.51 to -0.15, P = 0.001) and increased IMT (adjusted ß = 0.62, 95% CI: 0.54-1.90, P = 0.001 and adjusted ß = 0.43, 95% CI: 0.08-0.57, P = 0.011), respectively. CONCLUSIONS: Subjects with systemic inflammation were more insulin-resistant, and in nondiabetic predialysis CKD, IR and systemic inflammation were independently associated with endothelial dysfunction and atherosclerosis.