Chronic kidney disease (CKD) is a relentlessly progressive disease with a very high mortality mainly due to cardiovascular complications. Endothelial dysfunction is well documented in CKD and permanent loss of endothelial homeostasis leads to progressive organ damage. Most of the vast endothelial surface area is part of the microcirculation, but most research in CKD-related cardiovascular disease (CVD) has been devoted to macrovascular complications. We have reviewed all publications evaluating structure and function of the microcirculation in humans with CKD and animals with experimental CKD. Microvascular rarefaction, defined as a loss of perfused microvessels resulting in a significant decrease in microvascular density, is a quintessential finding in these studies. The median microvascular density was reduced by 29% in skeletal muscle and 24% in the heart in animal models of CKD and by 32% in human biopsy, autopsy and imaging studies. CKD induces rarefaction due to the loss of coherent vessel systems distal to the level of smaller arterioles, generating a typical heterogeneous pattern with avascular patches, resulting in a dysfunctional endothelium with diminished perfusion, shunting and tissue hypoxia. Endothelial cell apoptosis, hypertension, multiple metabolic, endocrine and immune disturbances of the uremic milieu and specifically, a dysregulated angiogenesis, all contribute to the multifactorial pathogenesis. By setting the stage for the development of tissue fibrosis and end organ failure, microvascular rarefaction is a principal pathogenic factor in the development of severe organ dysfunction in CKD patients, especially CVD, cerebrovascular dysfunction, muscular atrophy, cachexia, and progression of kidney disease. Treatment strategies for microvascular disease are urgently needed.

The relationships of cortisol with elevated blood pressure and insulin resistance are likely to be the result of a complex interplay of different mechanisms. We hypothesize that cortisol is associated with impaired microvascular function and that this contributes to cortisol-associated high blood pressure and insulin resistance. We examined 24 h urinary free cortisol excretion in 56 healthy adults (26 women). Blood pressure was assessed by 24 h ambulatory measurements. Insulin sensitivity was determined using the hyperinsulinaemic euglycaemic clamp technique. Skin capillary recruitment after arterial occlusion was visualized with videomicroscopy and endothelium-(in)dependent vasodilation was evaluated with iontophoresis of acetylcholine and sodium nitroprusside combined with laser Doppler fluxmetry. Men were characterized by higher urinary cortisol excretion [median (interquartile range), 162 (130–194) compared with 118 (99–156) nmol/24 h, P <0.05]. In women, but not in men, urinary cortisol excretion was associated with impaired capillary recruitment ( r =−0.66, P <0.001), higher systolic blood pressure ( r =0.64, P <0.001) and lower insulin sensitivity ( r =−0.43, P <0.05). Urinary cortisol excretion was not associated with endothelium-(in)dependent vasodilation in men or women. Regression analysis demonstrated that capillary recruitment statistically explained 37% of the association between urinary cortisol and blood pressure in women. Capillary recruitment did not explain part of the association between urinary cortisol and insulin sensitivity. In conclusion, urinary cortisol excretion is inversely associated with capillary recruitment in women, but not in men, and capillary recruitment explains part of the cortisol–blood pressure relationship. These data suggest that, in women, impairment of capillary function mediates some of the adverse effects of cortisol and thus may provide a target to prevent such adverse effects.

Insulin increases capillary recruitment in vivo and impairment of this may contribute to muscle insulin resistance by limiting either insulin or glucose delivery. In the present study, the effect of progressively decreased rat muscle perfusion on insulin action using graded occlusion with MS (microspheres; 15 μm in diameter) was examined. EC (energy charge), PCr/Cr (phosphocreatine/creatine ratio), AMPK (AMP-activated protein kinase) phosphorylation on Thr 172 (P-AMPKα/total AMPK), oxygen uptake, nutritive capacity, 2-deoxyglucose uptake, Akt phosphorylation on Ser 473 (P-Akt/total Akt) and muscle 2-deoxyglucose uptake were determined. Arterial injection of MS (0, 9, 15 and 30×10 6 MS/15 g of hindlimb muscle, as a bolus) into the pump-perfused (0.5 ml·min −1 ·g −1 of wet weight) rat hindlimb led to increased pressure (−0.5±0.8, 15.9±2.1, 28.7±4.6 and 60.3±9.4 mmHg respectively) with minimal changes in oxygen uptake. Nutritive capacity was decreased from 10.6±1.0 to 3.8±0.9 μmol·g −1 of muscle·h −1 ( P <0.05) with 30×10 6 MS. EC was unchanged, but PCr/Cr was decreased dose-dependently to 61% of basal with 30×10 6 MS. Insulin-mediated increases in P-Akt/total Akt decreased from 2.15±0.35 to 1.41±0.23 ( P <0.05) and muscle 2-deoxyglucose uptake decreased from 130±19 to 80±12 μg·min −1 ·g −1 of dry weight ( P <0.05) with 15×10 6 MS; basal P-AMPKα in the absence of insulin was increased, but basal P-Akt/total Akt and muscle 2-deoxyglucose uptake were unaffected. In conclusion, partial occlusion of the hindlimb muscle has no effect on basal glucose uptake and marginally impacts on oxygen uptake, but markedly impairs insulin delivery to muscle and, thus, insulin-mediated Akt phosphorylation and glucose uptake.

The morphology of gastrocnemius muscles was examined in RFPs (renal failure patients) being treated using HD (haemodialysis) and CAPD (continuous ambulatory peritoneal dialysis). RFPs ( n =24) volunteered to participate in the present study. Twelve RFPs (five women and seven men; mean age, 55 years) were undergoing CAPD treatment and 12 RFPs (two women and ten men; mean age, 62 years) were undergoing HD treatment. Muscle biopsies from gastrocnemius muscles were found not to differ ( P >0.05) in fibre type distribution, MyHC (myosin heavy chain) expression or fibre CSA (cross-sectional area) between the two groups. There were, however, significant differences ( P <0.05) in CC/F (capillary contact/fibre), C/F (capillary to fibre ratio) and cytochrome c oxidase activity. The HD group had 33% more CC/F, with a 19% higher C/F and 33% greater cytochrome c activity in glycolytic fibres (II) than the CAPD group. There were no apparent differences in age, gender, co-morbidity, self-reported physical activity or physical functioning between the two groups, which could account for the difference in muscle capillarity between the groups. The HD patients were, however, administered heparin as a routine part of the dialysis therapy. The possibility is discussed that heparin in combination with mild anaemia and acidosis may have augmented angiogenesis in the HD patients.

1. Pressure was measured within 28 capillaries of the nailfolds of nine patients with essential hypertension and in 33 capillaries of nine age- and sex-matched normotensive control subjects, using direct micropuncture, a dynamic servo-nulling system and computerized analysis. 2. Average pressure at the apex of the capillary was found to be elevated in the patients with hypertension (21.1 ± 4.9 mmHg compared with 13.0 ± 2.0 mmHg in the control subjects; mean ± SD, P < 0.01). If the two groups were combined, there was an overall correlation between average capillary pressure and mean blood pressure ( r = 0.68, P < 0.01, n = 18), but within each group separately there was no significant relation between these parameters. 3. There were also abnormalities in the waveforms of pulsations in capillary pressure in the group with hypertension, with an increased attenuation of high-frequency harmonics. Pulses appeared to be conducted more rapidly along the vascular tree in the patients with hypertension. 4. The elevation of capillary pressure in essential hypertension demonstrated in this study is in agreement with indirect evidence of capillary hyperfiltration provided by other studies which showed a reduced plasma volume and increased transcapillary escape rate of plasma proteins. 5. The finding of elevated capillary pressure demands the inclusion of the postcapillary segment (and possibly vascular density) in the resistance equation in essential hypertension.

1. Capillary blood pressure was measured in man using a dynamic servo-nulling system and direct micropuncture. This enabled assessments of the normal variations in pressure which influence fluid filtration and reabsorption. 2. Seventy-eight capillaries in 19 subjects were punctured in one of three positions around the capillary loop with the hand at the level of the sternal angle. Mean pressure around the loop fell from 37.7 ± 3.7 mmHg (arteriolar limb, mean ± sem , n = 12) to 19.4 ± 1.0 mmHg (apex, n = 25) to 14.6 ± 0.5 mmHg (venular limb, n = 41) at skin temperatures of 18.7–33.1°C. These values agree closely with Landis' original studies in 1930 [E. Landis (1930) Heart , 15 , 209–228]. 3. The mean filtration/reabsorption state of any particular capillary limb was not static because of cardiac, vasomotor and respiratory fluctuations in capillary pressure. From a total of 38 capillaries in which recordings were analysed for 30 s, the fluctuations in pressure were such that 27 capillaries probably had periods of both filtration and reabsorption. 4. Computerized superimposition and coherent averaging of trains of capillary pulses enabled an accurate description of the pulse waveform to be made in three capillaries. This was remarkably similar to waveforms from the radial artery, albeit at reduced amplitude (average 3.6 ± 3.4 mmHg, mean ± sd overall). The time for the pulse to travel between the radial artery and the finger capillary was approximately 10 ms, which implies a propagation velocity of several metres per second. 5. Fourteen long recordings of capillary pressure (mean 154 s) were subjected to computerized Fourier analysis and cross-correlation with other parameters. Low frequency fluctuations between 0.02 and 0.2 Hz (0.086 ± 0.05 Hz, mean ± sd ) correlated closely with vasomotion in simultaneously recorded (laser-Doppler) skin blood flow (0.080 ± 0.5 Hz), although they were not synchronous. Higher frequencies between 0.2 and 0.6 Hz (0.28 ± 0.03 Hz) correlated well with respiration (0.29 ± 0.03 Hz), were synchronous and probably relate to respiratory fluctuations in venous pressure. The dynamic system has thus enabled us to describe the considerable variations in normal capillary pressure and to relate this variability to physiological influences.

1. Relationships between labelled albumin disappearance rate (LADR), plasma volume, blood volume, plasma renin activity (PRA) and blood pressure (BP) were studied in normotensive control subjects and patients with hypertension of different aetiology and severity. In essential hypertensive patients without complications an inverse linear relationship was found between blood pressure and plasma or blood volume. 2. Very close inverse correlations were found between LADR and PRA in both normotensive subjects and patients with uncomplicated essential hypertension. LADR appears to be an excellent reference standard for PRA. 3. It is postulated that LADR mainly reflects the relation between circulating fluid and vascular capacitance tone. LADR is increased in hypertension and blood volume may still be inappropriately high.