Correction to: Phase-contrast magnetic resonance imaging to assess renal perfusion: a systematic review and statement paper.

The article Phase­contrast magnetic resonance imaging to assess renal perfusion: a systematic review and statement paper, written by Giulia Villa, Steffen Ringgaard, Ingo Hermann, Rebecca Noble, Paolo Brambilla, Dinah S. Khatir, Frank G. Zöllner, Susan T. Francis, Nicholas M. Selby, Andrea Remuzzi and Anna Caroli, was originally published electronically on the publisher's internet portal on 17 August 2019 without open access.

Phase-contrast magnetic resonance imaging to assess renal perfusion: a systematic review and statement paper.

OBJECTIVE: Phase-contrast magnetic resonance imaging (PC-MRI) is a non-invasive method used to compute blood flow velocity and volume. This systematic review aims to discuss the current status of renal PC-MRI and provide practical recommendations which could inform future clinical studies and its adoption in clinical practice. METHODOLOGY: A comprehensive search of all the PC-MRI studies in human healthy subjects or patients related to the kidneys was performed. RESULTS: A total of 39 studies were included in which PC-MRI was used to measure renal blood flow (RBF) alongside other derivative hemodynamic parameters. PC-MRI generally showed good correlation with gold standard methods of RBF measurement, both in vitro and in vivo, and good reproducibility. Despite PC-MRI not being routinely used in clinical practice, there are several clinical studies showing its potential to support diagnosis and monitoring of renal diseases, in particular renovascular disease, chronic kidney disease and autosomal dominant polycystic kidney disease. DISCUSSION: Renal PC-MRI shows promise as a non-invasive technique to reliably measure RBF, both in healthy volunteers and in patients with renal disease. Future multicentric studies are needed to provide definitive normative ranges and to demonstrate the clinical potential of PC-MRI, likely as part of a multi-parametric renal MRI protocol.

Aortic Calcification Affects Noninvasive Estimates of Central Blood Pressure in Patients with Severe Chronic Kidney Disease.

BACKGROUND: Central blood pressure (BP) assessed noninvasively considerably underestimates true invasively measured aortic BP in chronic kidney disease (CKD) patients. The difference between the estimated and the true aortic BP increases with decreasing estimated glomerular filtration rates (eGFR). The present study investigated whether aortic calcification affects noninvasive estimates of central BP. METHODS: Twenty-four patients with CKD stage 4-5 undergoing coronary angiography and an aortic computed tomography scan were included (63% males, age [mean ± SD ] 53 ± 11 years, and eGFR 9 ± 5 mL/min/1.73 m2). Invasive aortic BP was measured through the angiography catheter, while non-invasive central BP was obtained using radial artery tonometry with a SphygmoCor® device. The Agatston calcium score (CS) in the aorta was quantified on CT scans using the CS on CT scans. RESULTS: The invasive aortic systolic BP (SBP) was 152 ± 23 mm Hg, while the estimated central SBP was 133 ± 20 mm Hg. Ten patients had a CS of 0 in the aorta, while 14 patients had a CS >0 in the aorta. The estimated central SBP was lower than the invasive aortic SBP in patients with aortic calcification compared to patients without (mean difference 8 mm Hg, 95% CI 0.3-16; p = 0.04). The brachial SBP was lower than the aortic SBP in patients with aortic calcification compared to patients without (mean difference 10 mm Hg, 95% CI 2-19; p = 0.02). CONCLUSION: In patients with advanced CKD the presence of aortic calcification is associated with a higher difference between invasively measured central aortic BP and non-invasive estimates of central BP as compared to patients without calcifications.

Effects of additional vasodilatory or nonvasodilatory treatment on renal function, vascular resistance and oxygenation in chronic kidney disease: a randomized clinical trial.

AIM: Progression of chronic kidney disease (CKD) may be accelerated by tissue hypoxia due to impaired blood supply. This could be induced by small artery narrowing resulting in abnormally high intrarenal vascular resistance (RVR). We investigated whether a reduction in RVR achieved by adding vasodilating medical therapy (AVT) is superior to adding nonvasodilating medical therapy (AnonVT) regarding tissue oxygenation and preservation of kidney function. METHODS: Eighty-three grade 3 and 4 CKD patients [estimated glomerular filtration rate (GFR) 34.6 ml/min per 1.73 m] were randomized to either AVT with amlodipine and/or renin angiotensin blockade or AnonVT with the nonvasodilating beta-blocker metoprolol. Investigations were performed at baseline and after 18 months of therapy. Systemic vasodilation was documented in the forearm vasculature using resting venous occlusion plethysmography. GFR was measured as Chrome-EDTA plasma clearance. Using MRI, renal artery blood flow was measured for calculation of RVR and for estimating renal oxygenation (R2*). RESULTS: AVT and AnonVT achieved as planned similar blood pressure levels throughout the study. At follow-up, resistance had decreased by 7% (P < 0.05) and RVR by 12% (P < 0.05) in the AVT group, whereas in the AnonVT group, resistance increased by 39% (P < 0.01), whereas RVR remained unchanged. At follow-up, no significant differences in cortical or medullary R2* values between AVT and AnonVT were observed, and the GFR decline was similar in the two groups (3.0 vs. 3.3 ml/min per 1.73 m). CONCLUSION: Long-term intensified vasodilation treatment reduced peripheral and RVR, but this was not associated with improvement of R2* or protection against loss of kidney function in CKD patients.

Arterial stiffness and peripheral vascular resistance in offspring of hypertensive parents: influence of sex and other confounders.

AIM: Established essential hypertension is associated with increased arterial stiffness and peripheral resistance, but the extent of vascular changes in persons genetically predisposed for essential hypertension is uncertain. METHODS: Participants from the Danish Hypertension Prevention Project (DHyPP) (both parents hypertensive) (n = 95, 41 ±â€Š1 years, 53% men) were compared with available spouses (n = 45, 41 ±â€Š1 years) using measurements of ambulatory blood pressure (BP), left ventricular mass index (LVMI), pulse wave velocity, central BP and augmentation index (AIx) in addition to forearm resting and minimal resistance [forearm resting vascular resistance (Rrest) and forearm minimal vascular resistance (Rmin)]. RESULTS: DHyPP patients with participating spouses had higher 24-h mean BP (94 ±â€Š1 vs. 88 ±â€Š1 mmHg, P < 0.01), LVMI (94 ±â€Š3 vs. 80 ±â€Š2 g/m, P < 0.01), central SBP (121 ±â€Š2 vs. 111 ±â€Š2 mmHg, P < 0.01) and AIx (16.0 ±â€Š1.2 vs. 10.5 ±â€Š1.7%, P < 0.01), but similar carotid-femoral pulse wave velocity (7.5 ±â€Š0.2 vs. 7.1 ±â€Š0.2 m/s), Rrest (53 ±â€Š3 vs. 51 ±â€Š3 mmHg/ml/min/100 ml) and log Rmin (0.58 ±â€Š0.02 vs. 0.55 ±â€Š0.02 mmHg/ml/min/100 ml) when compared with spouses. Using multiple linear regression analysis (adjusting for sex, age, BMI, creatinine clearance and 24-h BP, heart rate and sodium excretion) AIx and LVMI remained elevated in DHyPP patients [4.2% (0.7; 7.7), P = 0.02 and 6.3 g/m (0.7; 11.9), P = 0.03]. For the entire DHyPP cohort AIx, Rrest and Rmin were higher in women than men (P < 0.01), and the same was true for AIx and Rmin among spouses (P < 0.05). Furthermore, AIx was linearly associated with Rrest and Rmin. CONCLUSION: Young to middle-aged individuals genetically predisposed for essential hypertension display increased AIx and LVMI, although vascular stiffness and peripheral resistance are still normal.

Urine liver fatty acid binding protein and chronic kidney disease progression.

Excretion of the tubular protein liver fatty acid binding protein (L-FABP) is a potential novel biomarker of renal dysfunction. We examined whether urine L-FABP excretion adds prognostic information to the well-established risk markers, blood pressure (BP), albumin excretion and baseline GFR, regarding progression of chronic kidney disease (CKD). In a prospective study design a cohort of 74 stage 3-4 CKD patients (age 61 ± 13 years) were included. Glomerular filtration ratio (GFR, 51Cr-EDTA-clearance), 24-hour ambulatory BP, 24-hour urinary albumin/creatinine ratio (UAC) and urinary L-FABP/creatinine ratio (U-L-FABP/C) were determined at baseline and after 18 months of follow-up. For comparison 25 age-matched healthy controls were included. The U-L-FABP/C was elevated in CKD patients when compared to controls (mean U-L-FABP/C 2.3 [95% CI 1.7-2.9] µg/mmol vs 0.6 [0.5-0.7] µg/mmol, p < .001). In CKD patients, log U-L-FABP/C at baseline and at follow-up were positively associated (Pearson correlation coefficient r = 0.74, p < .001). Baseline log U-L-FABP/C was negatively correlated with baseline GFR (r = -0.32, p < .001) and directly correlated with UAC (r = 0.67, p < .001). The relative change in GFR from baseline to follow-up correlated with baseline UAC (p < .001), 24-hour systolic BP (p = 0.05) and log U-L-FABP/C (p < .001). Using multiple regression analysis adjusting for baseline GFR, UAC, BP, age and gender, baseline log U-L-FABP/C was associated with a decline in GFR only in patients with UAC <3 mg/mmol (n = 29, p = 0.001) and not in patients with UAC ≥3 mg/mmol (n = 44, p = 0.21). In conclusion urine L-FABP/C is permanently elevated in CKD patients, but only associated with GFR decline in those without albuminuria.

Estimated aortic blood pressure based on radial artery tonometry underestimates directly measured aortic blood pressure in patients with advancing chronic kidney disease staging and increasing arterial stiffness.

Central blood pressure (BP) can be assessed noninvasively based on radial tonometry and may potentially be a better predictor of clinical outcome than brachial BP. However, the validity of noninvasively obtained estimates has never been examined in patients with chronic kidney disease (CKD). Here we compared invasive aortic systolic BP (SBP) with estimated central SBP obtained by radial artery tonometry and examined the influence of renal function and arterial stiffness on this relationship. We evaluated 83 patients with stage 3 to 5 CKD (mean estimated glomerular filtration rate [eGFR] 30 ml/min/1.73 m(2)) and 41 controls without renal disease undergoing scheduled coronary angiography. BP in the ascending aorta was measured through the angiography catheter and simultaneously estimated using radial tonometry. The mean difference between estimated central and aortic SBP was -13.2 (95% confidence interval -14.9 to -11.4) mm Hg. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cf-PWV) and was significantly increased in CKD patients compared with (versus) control patients (mean 10.7 vs. 9.3 m/s). The difference in BP significantly increased 1.0 mm Hg for every 10 ml/min decrease in eGFR and by 1.6 mm Hg per 1 m/s increase in cfPWV. Using multivariate regression analysis including both eGFR and cfPWV, the difference between estimated central and invasive aortic SBP was significantly increased by 0.7 mm Hg. For the entire cohort brachial SBP significantly better reflected invasive SBP than estimated SBP. Thus, tonometry-based estimates of central BP progressively underestimate invasive central SBP with decreasing renal function and increasing arterial stiffness in CKD patients.

Evaluation of Renal Blood Flow and Oxygenation in CKD Using Magnetic Resonance Imaging.

BACKGROUND: Animal studies suggest that progression of chronic kidney disease (CKD) is related to renal hypoxia. With renal blood supply determining oxygen delivery and sodium absorption being the main contributor to oxygen consumption, we describe the relationship between renal oxygenation, renal artery blood flow, and sodium absorption in patients with CKD and healthy controls. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 62 stable patients with CKD stages 3 to 4 (mean age, 61±13 [SD] years) and 24 age- and sex-matched controls. PREDICTORS: CKD versus control status. OUTCOMES: Renal artery blood flow, tissue oxygenation (relative changes in deoxyhemoglobin concentration of the renal medulla [MR2*] and cortex [CR2*]), and sodium absorption. MEASUREMENTS: Renal artery blood flow was determined by phase-contrast magnetic resonance imaging (MRI); MR2* and CR2* were determined by blood oxygen level-dependent MRI. Ultrafiltered and reabsorbed sodium were determined from measured glomerular filtration rate (mGFR) and 24-hour urine collections. RESULTS: mGFR in patients was 37% that of controls (36±15 vs 97±23 mL/min/1.73 m(2); P < 0.001), and reabsorbed sodium was 37% that of controls (6.9 vs 19.1 mol/24 h; P < 0.001). Single-kidney patient renal artery blood flow was 72% that of controls (319 vs 443 mL/min; P < 0.001). Glomerular filtration fraction was 9% in patients and 18% in controls (P < 0.001). Patients and controls had similar CR2* (13.4 vs 13.3 s(-1)) and medullary MR2* (26.4 vs 26.5 s(-1)) values. Linear regression analysis demonstrated no associations between R2* and renal artery blood flow or sodium absorption. Increasing arterial blood oxygen tension by breathing 100% oxygen had very small effects on CR2*, but reduced MR2* in both groups. LIMITATIONS: Only renal artery blood flow was determined and thus regional perfusion could not be related to CR2* or MR2*. CONCLUSIONS: In CKD, reductions of mGFR and reabsorbed sodium are more than double that of renal artery blood flow, whereas cortical and medullary oxygenation are within the range of healthy persons. Reduction in glomerular filtration fraction may prevent renal hypoxia in CKD.

Differential effects of age on large artery stiffness and minimal vascular resistance in normotensive and mildly hypertensive individuals.

Large artery stiffness and small artery structural changes are both cardiovascular risk factors. Arterial stiffness increases with age and blood pressure (BP), but it is unclear in which way large artery pulse wave velocity (PWV) and peripheral vascular resistance are related and whether age has any influence. In a cross-sectional study, PWV and forearm minimum vascular resistance (Rmin ) was compared with emphasis on the impact of age. Normotensive (n = 53) and untreated hypertensive (n = 23) subjects were included based on 24-h BP measurements. Age ranged from 21 to 79 years with an even distribution from each age decade. PWV was assessed using tonometry. Forearm Rmin was measured by venous occlusion plethysmography at maximal vasodilatation induced by 10 min of ischaemia in combination with skin heating and hand grip exercise. In both normotensive and hypertensive subjects, PWV correlated significantly with age and BP. Based on median age, both groups were assigned into two equally large subgroups. Normotensive older (66 ± 7 years) and younger (35 ± 10 years) persons had different carotid-femoral PWV (7.9 ± 1.8 versus 5.7 ± 0.9 m/s, P<0.01), but similar Rmin values (3.7 ± 0.9 versus 3.6 ± 1.2 mmHg/ml/min/100 ml). Hypertensive older (63 ± 6 years) and younger (40 ± 10 years) also had different PWV (8.0 ± 1.5 versus 6.7 ± 1.1 m/s, P<0.05), but the older had lower Rmin (3.1 ± 0.8 versus 4.7 ± 2.2 mmHg/ml/min/100 ml, P<0.05). In a regression analysis adjusting for age, BP, gender and heart rate, no correlation was seen between PWV and Rmin . The data suggest that age differentially affects PWV and Rmin and that BP can increase in older persons without affecting Rmin .

Reproducibility of MRI renal artery blood flow and BOLD measurements in patients with chronic kidney disease and healthy controls.

PURPOSE: Determine the reproducibility of renal artery blood flow (RABF) and blood-oxygenation level dependent (R2 *) in patients with chronic kidney disease (CKD) and healthy controls. MATERIALS AND METHODS: RABF and R2 * were measured in 11 CKD patients and 9 controls twice with 1- to 2-week interval. R2 * in the cortex and medulla were determined after breathing atmospheric air and 100% oxygen. Reproducibility was evaluated by coefficients of variation (CV), limits of agreements and intra-class coefficient calculated by variance components by maximum likelihood modeling. RESULTS: Single-kidney RABF (mL/min) for patients was: 170 ± 130 and 186 ± 137, and for controls: 365 ± 119 and 361 ± 107 (P < 0.05 versus patients), for first and second scans, respectively. RABF measurements were reproducible with a CV of 12.9% and 8.3% for patients and controls, respectively. Renal cortical R2 * was: 13.6 ± 0.9 and 13.5 ± 1.2 in patients (CV = 8.0%), and 13.8 ± 1.6 and 14.0 ± 1.5 in controls (CV = 5.6%), while medullary R2 *(s(-1) ) was: 26.9 ± 2.0 and 27.0 ± 4.0 (CV = 8.0%) in patients, and 26.0 ± 2.4 and 26.1 ± 2.1 (CV = 3.6%) in controls, for first and second scans, respectively. In both groups R2 * in medulla decreased after breathing 100% oxygen. CONCLUSION: The reproducibility was high for both RABF and R2 * in patients and controls, particularly in the cortex. Inhalation of 100% oxygen reduced medullary R2 *.

The involvement of growth hormone (GH), insulin-like growth factors (IGFs) and vascular endothelial growth factor (VEGF) in diabetic kidney disease.

At present, diabetic kidney disease affects about 15-25 % of patients with type 1 diabetes (T1D) and 30-40 % of patients with type 2 diabetes (T2D). Several decades of extensive research have elucidated various pathways to be implicated in the development of diabetic kidney disease. These include metabolic factors beyond blood glucose (e.g. advanced glycation endproducts (AGEs)), haemodynamic factors (e.g. the renin angiotensin system (RAS)), intracellular signaling molecule proteins (e.g. protein kinase C (PKC)) and growth factors/cytokines (e.g. growth hormone (GH), insulin-like growth factors (IGFs), transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF)). This review focuses on the role of three of these growth factors, i.e. GH, IGFs and VEGF. A brief discussion of each system is followed by description of its expression in the normal kidney. Then, for each system, in vitro, experimental and clinical evidence addressing the role of the system in diabetic kidney disease is presented. The interplay of each system to other potential pathways will also be addressed. Finally, well-known and potential therapeutic strategies targeting the GH/IGF and VEGF systems in a specific or indirect way will discussed.