Dietary nitrate load lowers blood pressure and renal resistive index in patients with chronic kidney disease: A pilot study.

Beetroot has a high concentration of inorganic nitrate, which can serially reduced to form nitrite and nitric oxide (NO) after oral ingestion. Increased renal resistive index (RRI) measured by Doppler ultrasonography is associated with higher cardiovascular mortality in hypertensive patients with reduced renal function over time defined as chronic kidney disease (CKD). Our aim was to investigate whether the supplementation of dietary nitrate by administration of beetroot juice is able to reduce blood pressure and renal resistive index (RRI) as prognostic markers for cardiovascular mortality in CKD patients. In a cross-over study design, 17 CKD patients were randomized to either a dietary nitrate load (300 mg) by highly concentrated beetroot juice (BJ) or placebo (water). Hemodynamic parameters as well as plasma nitrate concentration and RRI were measured before and 4 h after treatment. In this cohort, CKD was mainly caused by hypertensive or diabetic nephropathy. The mean eGFR was 41.6 ± 12.0 ml/min/m2. Plasma nitrate concentrations were significantly increased after ingestion of BJ compared to control. Peripheral systolic and diastolic blood pressure as well as mean arterial pressure (MAP) were significantly reduced secondary to the dietary nitrate load compared to control (e.g. ΔMAPBJ = -8.2 ± 7.6 mmHg vs. ΔMAPcontrol = -2.2 ± 6.0 mmHg, p = 0.012). BJ also led to significantly reduced RRI values (ΔRRIBJ = -0.03 ± 0.04 versus ΔRRIcontrol = 0.01 ± 0.04; p = 0.017). Serum potassium levels were not altered secondary to the treatment. In this study, administration of the nitrate donor BJ led to significantly reduced RRI values and peripheral blood pressure which might be explained by release of the vasodilatator NO after oral intake. Whether supplementation of dietary nitrate in addition to routine pharmacologic therapy is able to decelerate progression of cardiovascular and renal disease in CKD, remains to be investigated.

Microcirculatory marker for the prediction of renal end points: a prospective cohort study in patients with chronic kidney disease stage 2 to 4.

Retinal arteriolar narrowing reflects aging, hypertension, chronic kidney disease (CKD), and other vascular processes. We examined the predictive value of retinal arteriolar narrowing alone and in combination with albuminuria on renal disease progression in CKD. A white CKD stage 2 to 4 cohort of 164 men and women (60.8±13.8 years) underwent retinal photography and determination of albuminuria. The calibers of all retinal arterioles were measured after digital conversion of the photographs. Cases of incident renal end points defined as 50% renal function loss and start of renal replacement therapy were identified and validated by case record reviews. Over an average period of 1410 (range, 106-1606) days, 25 patients with CKD had incident renal end points. Kaplan-Meier analysis revealed that patients with CKD within the tertile of narrowest arterioles had more renal end points (log-rank P<0.001). Cox regression analysis confirmed this before (ß=1.183±0.411) and after adjusting for age and baseline renal function (ß=1.204±0.416). With respect to renal end points, a significant interaction was present between narrow arterioles and albuminuria. The relative risk for renal end points of narrow arterioles was 3.7 (1.7-8.4), of albuminuria was 5.4 (2.5-12.0), and of combined narrow arterioles and albuminuria was 16.2 (4.6-57.2). Hence retinal arteriolar narrowing is related to incident renal end points. Narrow arterioles and albuminuria reveal a synergistic predictive value. The findings support a leading role of the microvasculature in the pathogenesis of renal disease progression. They also suggest that retinal photography in combination with albuminuria determination may be useful for risk stratification with respect to renal disease progression in patients with CKD stage 2 to 4.

Aortic to brachial pulse pressure amplification as functional marker and predictor of renal function loss in chronic kidney disease.

Pulse pressure amplification (PPA) reflects large artery function. Its contribution in chronic kidney disease (CKD) remains uncertain. The authors assessed PPA in CKD progression in patients with CKD stage 2 to 4 (n=128) and 89 controls (follow-up: 42 months). PPA was reduced in CKD patients as compared with control patients and associated with decline in renal function. Sixteen renal endpoints, defined by 50% loss of renal function or start of renal replacement therapy, were detected. In Cox regression analysis, PPA, estimated glomerular filtration rate, and proteinuria predicted renal endpoints. Patients with CKD stage 4 and low PPA had the highest risk for developing renal endpoints (unadjusted 8.1; 2.4-27.7 and adjusted for age and proteinuria 5.6; 1.5-21.9, log-rank P<.001). Taken together, PPA is reduced in CKD and is associated with declining renal function. In addition, low PPA predicts renal endpoints in severe CKD. Furthermore, this study emphasizes the role of systolic blood pressure as a major determinant of PPA.

Serum myeloid-related protein 8/14 complex is associated with microalbuminuria in patients with type 2 diabetes.

OBJECTIVES: Microalbuminuria (MA) is associated independently with cardiovascular risk and progression of renal disease in patients with diabetes and the normal population. MA is an accepted factor for microvascular defects, in particular in patients with diabetes, and is associated with inflammation. Activated transmigrating macrophages are key cells in these inflammatory processes. Based on the theory that myeloid-related protein 8/14 complex (MRP8/14) is secreted by transmigrating macrophages, we hypothesized that MA was accompanied by elevated MRP8/14 and investigated whether MA predicts MRP8/14 in patients with type 2 diabetes. METHODS: A total of 86 men with type 2 diabetes were grouped according to urinary albumin excretion in normoalbuminuria and MA. Serum MRP8/14 levels were measured by enzyme-linked immunosorbent assay. Established cardiovascular risk factors were quantified in both groups and compared with urinary albumin excretion. RESULTS: Albuminuria (mg/day) was positively associated with MRP8/14 (r = 0.34) and systemic blood pressure (r = 0.33). Patients with type 2 diabetes and MA demonstrated significantly higher MRP8/14 levels than patients with normoalbuminuria [median (interquartile range), 1.24 (0.97-2.28) µg/ml versus 0.97 (0.67-1.35) µg/ml, p < 0.05]. Serum creatinine levels, systolic blood pressure (SBP), very low density lipoprotein levels and the incidence of hypertension and coronary artery disease were significantly higher in the group with MA. Both groups did not differ significantly in other cardiovascular risk factors. MA was an independent predictor of serum MRP8/14 levels (ß = 0.454) as well as SBP (ß = 0.625) and haemoglobin A1c (ß = 0.322). CONCLUSION: Our data demonstrate that albumin excretion is associated with the process of macrophage activation determined by MRP8/14 levels. These data not only suggest tissue inflammation as a factor for elevated cardiovascular risk in patients with type 2 diabetes, they further point to a role of macrophage activation in this process.

Aortic pulse wave velocity predicts mortality in chronic kidney disease stages 2-4.

BACKGROUND: Chronic kidney disease (CKD) is characterized by aortic stiffness and increased cardiovascular mortality. In end-stage renal disease, aortic stiffness predicts mortality, whereas this role remains uncertain in mild-to-moderate CKD. We aimed to investigate whether aortic pulse wave velocity (aPWV) predicts mortality and renal disease progression in CKD patients. METHODS: We enrolled 135 CKD patients stages 2-4 [estimated glomerular filtration rate (eGFR): 41.1 (28.5-61.6) ml/min per 1.73  m] in the study and assessed aPWV. The combined renal end-point was defined as at least 50% decline in renal function and/or start of renal replacement therapy. RESULTS: During the observational period of 42 (30-50) months six patients were lost of follow-up, 13 patients died and 16 patients reached the combined renal end-point. Stratification according to the mean of aPWV (10  m/s), Kaplan-Meier analysis revealed increased mortality with aPWV ≥10  m/s (log-rank P < 0.05). Stepwise logistic regression analysis confirmed aPWV as an independent predictor for mortality in CKD stage 2-4. The hazard ratio of mortality in the cohort with an aPWV at least 10  m/s was 5.1 (1.1-22.9). By contrast, Kaplan-Meier analysis revealed no effect of aPWV on the combined renal end-point (log-rank P = 0.90). DISCUSSION: These results provide the first direct evidence that in patients with CKD stage 2-4, increased aortic stiffness determined by aPWV is a strong independent predictor of all-cause mortality.

MRP8/14 is associated with systemic inflammation in stable coronary atherosclerosis in men.

BACKGROUND: MRP8/14, a secreted heterodimeric protein complex secreted upon phagocyte activation, plays an important role in atherogenesis and vascular injury. Phagocyte activation is crucially involved in the development of atherosclerotic processes, and MRP8/14 levels have also been linked to acute cardiovascular events. We investigated whether circulating MRP8/14 correlates to chronic coronary artery disease (CAD) stages in this observational, cross-sectional study. METHODS AND RESULTS: A total of 240 male subjects undergoing elective coronary angiography were included in the study. CAD was present in 166 individuals, whereas 74 subjects were classified without prevalent CAD (control subjects). The atherosclerotic burden was obtained by three independent angiographic scores: the Severity, Gensini and Extent Score. Serum MRP8/14 levels were measured by ELISA. They were associated with hs-CRP, IL-6 and fibrinogen levels (r = 0·43, r = 0·40 and r = 0·44, respectively; all P < 0·001). However, MRP8/14 was neither associated with any other cardiovascular disease risk factor nor did serum levels differ between patients with stable CAD [0·82 (0·55-1·14) µg mL(-1) ] and control subjects [0·91 (0·63-1·30) µg mL(-1) ; P = 0·69]. Moreover, atherosclerotic wall irregularities did not demonstrate any association with circulating MRP8/14. CONCLUSIONS: The phagocyte activation marker MRP8/14 is significantly associated with markers of systemic inflammation in male patients with CAD. However, we were unable to find a correlation between circulating MRP8/14 complex and stable CAD.

Non-diabetic chronic kidney disease influences retinal microvasculature.

BACKGROUND: Chronic kidney disease (CKD) is characterized by increased cerebrovascular risk. Retinal vessel analysis (RVA) is an accepted measure of the retinal microvasculature, mirrors hypertension and cardiovascular morbidity. Epidemiological studies demonstrate narrower retinal arterioles with declining renal function. The effect of CKD on the retinal microcirculation remains uncertain. METHODS: RVA was performed in 34 non-diabetic CKD patients and 33 age-matched volunteers with normal renal function. Retinal photographs were digitized, vascular lumen diameters measured and the ratio of retinal arteriolar and venular lumen diameters (AVR) calculated. Office blood pressure (BP) was measured and cardiovascular risk factors assessed. RESULTS: AVR was lower in CKD patients as compared to age-matched volunteers (0.77 +/- 0.05 vs. 0.86 +/- 0.06; p < 0.05). In particular, retinal arterioles were narrower in CKD patients as compared to volunteers (169.6 +/- 20.4 vs. 189.5 +/- 14.2 microm; p < 0.01). In CKD, estimated glomerular filtration rate, BP and renin-angiotensin system blocker independently predicted AVR. Moreover, retinal arteriolar diameter independently predicted renal function (beta = 0.33; p < 0.05). CONCLUSION: CKD narrowed retinal arterioles suggesting an extended effect of CKD on the cerebral microvasculature. This study shows that in CKD patients, renal function, BP status and renin-angiotensin system blockade independently predict AVR as a marker for microvascular damage and that retinal microvasculature can predict renal function.

Myeloid-related protein 8/14 complex describes microcirculatory alterations in patients with type 2 diabetes and nephropathy.

BACKGROUND: Inflammation contributes to cardiovascular complications in type 2 diabetes, which are often characterized by microvascular alterations. We investigated whether myeloid-related protein 8/14 complex (MRP8/14) secreted by transmigrating monocytes and granulocytes may represent a biomarker for microvascular alterations in patients with type 2 diabetes and nephropathy. METHODS: MRP8/14 was measured in 43 patients with type 2 diabetes and nephropathy. Additionally, the inflammatory markers Interleukin-6 (IL-6), Tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP) were quantified. To detect microvascular alterations proteinuria and retinal vessel caliber were used as classical and novel marker, respectively. Proteinuria was quantified by protein-creatinine ratio (PCR); retinal vessel caliber was quantified after retina photography on digitalized retina pictures. RESULTS: MRP8/14 was positively associated with inflammation (r = 0.57), proteinuria (r = 0.40) and retinal arterial caliber (r = 0.48). Type 2 diabetic patients with MRP8/14 values above the median of 5.8 microg/ml demonstrated higher proteinuria and larger retinal artery caliber than patients with MRP8/14 values below the median (logPCR: -0.51 +/- 0.52 versus -0.96 +/- 0.46, P < 0.01; retinal artery lumen (microm): 178.3 +/- 14.1 versus 162.7 +/- 14.9 P < 0.01). Both groups did not differ with regard to metabolic factors and blood pressure. MRP8/14 was an independent predictor of retinal artery caliber in multivariate stepwise regression analysis (beta = 0.607) and was positively associated with IL-6 (r = 0.57, P < 0.001) and TNF-alpha (r = 0.36, P < 0.05). CONCLUSION: MRP8/14--a marker for transendothelial migration--describes not only the state of inflammation in diabetic nephropathy, but additionally the degree of microvascular alterations in the glomerular and retinal bed. Therefore, MRP8/14 may be a potentially selective novel biomarker for microcirculatory defects in diabetic nephropathy.

An increase in myeloid-related protein serum levels precedes acute renal allograft rejection.

Upon interaction with activated endothelium, monocytes and neutrophils form complexes of myeloid-related protein 8 (MRP8) (S100A8) and MRP14 (S100A9), two members of the calcium-binding S100 family that are secreted during transendothelial migration. In a pilot study of 20 renal transplant recipients and a validation study of 36 renal transplant recipients, MRP8/14 serum levels were measured with an enzyme-linked immunosorbent assay for 28 d, associated with C-reactive protein and creatinine serum levels, and grouped according to biopsy-proven acute rejection. Serum levels of MRP8/14 but not C-reactive protein were significantly increased for several days during the first 2 wk for the acute rejection groups in both studies (P < 0.005, on day 6 after transplantation). As determined by using receiver operating characteristic curves, the optimal cutoff for 100% specificity and high sensitivity (67%) for acute rejection on day 6 after transplantation was calculated to be 4.2 microg/ml for MRP8/14 in the pilot study; this value was confirmed in the validation study. Positive MRP8/14 serum levels preceded acute rejection episodes by a median of 5 d. A 3-d course of intravenous methylprednisolone therapy reduced prerejection MRP8/14 serum levels from 5.7 microg/ml to 3.3 microg/ml (P < 0.05). All MRP8/14 serum levels were below the cutoff during urinary tract infections, delayed graft function, or cytomegalovirus infections, and these values did not differ significantly from control values. It is concluded that the MRP8/14 complex is a very early serum marker suitable for monitoring of acute rejection with high sensitivity and specificity.