Thrombotic microangiopathy (TMA) is a pattern of endothelial damage that can be found in association with diverse clinical conditions such as malignant hypertension. Although the pathophysiological mechanisms differ, accumulating evidence links complement dysregulation to various TMA syndromes and in particular the atypical hemolytic uremic syndrome. Here, we evaluated the role of complement in nine consecutive patients with biopsy-proven renal TMA attributed to severe hypertension. Profound hematologic symptoms of TMA were uncommon. In six out of nine patients, we found mutations C3 in three, CFI in one, CD46 in one, and/or CFH in two patients either with or without the risk CFH-H3 haplotype in four patients. Elevated levels of the soluble C5b-9 and renal deposits of C3c and C5b-9 along the vasculature and/or glomerular capillary wall, confirmed complement activation in vivo. In contrast to patients without genetic defects, patients with complement defects invariably progressed to end-stage renal disease, and disease recurrence after kidney transplantation seems common. Thus, a subset of patients with hypertension-associated TMA falls within the spectrum of complement-mediated TMA, the prognosis of which is poor. Hence, testing for genetic complement abnormalities is warranted in patients with severe hypertension and TMA on renal biopsy to adopt suitable treatment options and prophylactic measures.

Intrapatient CV of Tac AUC0-24 improved after converting from Tac BID to Tac QD in stable renal transplant patients, especially in patients with the CYP3A5*1/3 genotype. Given the very strict protocol of this PK study, this improvement is most likely due to the different intrinsic PK properties of Tac QD and Tac BID.

Shear stress (SS) is thought to be constant throughout the vascular system. Evidence for this supposition is scarce, however. To verify this hypothesis in vivo, we assessed common carotid (CCA) and brachial artery (BA) peak and mean wall shear rate (SR) noninvasively in 10 healthy volunteers (23.7 +/- 3.4 yr) with an ultrasound SR estimation system. SS was estimated from SR and calculated whole blood viscosity. SR was higher (P < 0.05) in the CCA (mean: 359 +/- 111 s(-1); peak: 1,047 +/- 345 s(-1)) than in the BA (mean: 95 +/- 24 s(-1); peak: 770 +/- 170 s(-1)). Whole blood viscosity was higher in the BA than in the CCA (5.1 +/- 0.7 vs. 3.3 +/- 0.6 mPa. s; P < 0.001). Peak SS did not differ between the CCA and the BA, whereas mean SS was significantly higher in the CCA (1.15 +/- 0.21 Pa) than in the BA (0.48 +/- 0.15 Pa; P < 0.001). These results demonstrate that BA SS strongly deviates from CCA SS in vivo.

Objectives: Physical inactivity in end-stage renal disease (ESRD) patients is associated with increased mortality, and might be related to abnormalities in body composition (BC) and physical performance. It is uncertain to what extent starting dialysis influences the effects of ESRD on physical activity (PA). This study aimed to compare PA and physical performance between stage 5 chronic kidney disease (CKD-5) non-dialysis and dialysis patients, and healthy controls, to assess alterations in PA during the transition from CKD-5 non-dialysis to dialysis, and to relate PA to BC. Methods: For the cross-sectional analyses 44 CKD-5 non-dialysis patients, 29 dialysis patients, and 20 healthy controls were included. PA was measured by the SenseWear™ pro3. Also, the walking speed and handgrip strength (HGS) were measured. BC was measured by the Body Composition Monitor©. Longitudinally, these parameters were assessed in 42 CKD-5 non-dialysis patients (who were also part of the cross-sectional analysis), before the start of dialysis and 6 months thereafter. Results: PA was significantly lower in CKD-5 non-dialysis patients as compared to that in healthy controls but not as compared to that in dialysis patients. HGS was significantly lower in dialysis patients as compared to that in healthy controls. Walking speed was significantly lower in CKD-5 non-dialysis patients as compared to that in healthy controls but not as compared to that in dialysis patients. Six months after starting dialysis, activity related energy expenditure (AEE) and walking speed significantly increased. Conclusions: PA is already lower in CKD-5 non-dialysis patients as compared to that in healthy controls and does not differ from that of dialysis patients. However, the transition phase from CKD-5 non-dialysis to dialysis is associated only with a modest improvement in AEE.

Background Cardiovascular disease (CVD) related mortality and morbidity are high in end-stage renal disease (ESRD). The pathophysiology of CVD in ESRD may involve non-traditional CVD risk factors, such as accumulation of advanced glycation endproducts (AGEs), dicarbonyls, endothelial dysfunction (ED) and low-grade inflammation (LGI). However, detailed data on the relation of AGEs and dicarbonyls with ED and LGI in ESRD are limited. Methods We examined cross-sectional Spearman’s rank correlations of AGEs and dicarbonyls with serum biomarkers of ED and LGI in 43 individuals with chronic kidney disease (CKD) stage 5 not on dialysis (CKD5-ND). Free and protein-bound serum AGEs ( N ∈ -(carboxymethyl)lysine (CML), N ∈ -(carboxyethyl)lysine (CEL), N δ -(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)) and serum dicarbonyls (glyoxal, methylglyoxal, 3-deoxyglucosone) were analyzed with tandem mass spectrometry, and tissue AGE accumulation was estimated by skin autofluorescence (SAF). Further, serum biomarkers of ED and LGI included sVCAM-1, sE-selectin, sP-selectin, sThrombomodulin, sICAM-1, sICAM-3, hs-CRP, SAA, IL-6, IL-8 and TNF-α. Results After adjustment for age, sex and diabetes status, protein-bound CML was positively correlated with sVCAM-1; free CEL with sVCAM-1 and sThrombomodulin; glyoxal with sThrombomodulin; and methylglyoxal with sVCAM-1 (correlation coefficients ranged from 0.36 to 0.44). In addition, free CML was positively correlated with SAA; protein-bound CML with IL-6; free CEL with hs-CRP, SAA and IL-6; free MG-H1 with SAA; protein-bound MG-H1 with IL-6; and MGO with hs-CRP and IL-6 (correlation coefficients ranged from 0.33 to 0.38). Additional adjustment for eGFR attenuated partial correlations of serum AGEs and serum dicarbonyls with biomarkers of ED and LGI. Conclusions In individuals with CKD5-ND, higher levels of serum AGEs and serum dicarbonyls were related to biomarkers of ED and LGI after adjustment for age, sex and diabetes mellitus. Correlations were attenuated by eGFR, suggesting that eGFR confounds and/or mediates the relation of serum AGEs and dicarbonyls with ED and LGI.