Objective Glucoraphanin, a precursor of sulforaphane (SFN), is found in high concentrations in broccoli sprout extract (BSE) and has been shown to have antioxidant effects and to improve glucose control in type 2 diabetes (T2D). This randomized controlled trial (RCT) aimed to investigate whether BSE could improve glucose control in patients with chronic kidney disease (CKD) and T2D. Design and methods This multicentre double-blind placebo-controlled RCT included adult patients with T2D and CKD stages 3b-4. Participants were randomized to receive an incremental dose of BSE (maximum 150 μmol/day BSE (750 μmol SFN)) or placebo. The use BSE or placebo lasted 12 weeks (week 1 to 13) plus 8 weeks (week 14 to 21) with no intervention. The main outcome was improvement in glycemic control. Results 99 patients were included, and 91 completed the study. Mean age was 74±7 years, 69% men and mean estimated glomerular filtration rate (eGFR) 28±7 mL/min/1.73 m2. There were no significant differences in baseline characteristics between the groups. In an intention-to-treat analysis, there were no statistically significant differences between groups in fasting glucose, insulin or HbA1c levels after 13 weeks or at 21 weeks of follow-up (end of study). Similarly, no statistically significant differences were observed between both groups in these variables in a per protocol analysis. Conclusion In patients with T2D and moderate CKD, 12 weeks of treatment with BSE with progressing dose (50 to 150 μmol/day BSE) did not result in statistically significant changes in measures related with glycemic control.

BACKGROUND:Discordance between cystatin C- and creatinine-based estimated glomerular filtration rate (eGFR) has been linked to adverse outcomes. A low eGFRcys/eGFRcr-ratio, conceptualized as selective glomerular hypofiltration syndrome (SGHS), has been hypothesized to reflect early metabolic kidney vulnerability, although non-glomerular filtration rate determinants may also contribute. We investigated associations of dysglycemia and insulin resistance with the eGFRcys/eGFRcr-ratio in a general population. METHODS:In 28,078 participants aged 50-64 years from the Swedish CArdioPulmonary bioImage Study, we assessed glycemic status (normoglycemia, prediabetes, and diabetes), hemoglobin A1c (HbA1c), fasting glucose, and insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR]). Outcomes were the continuous eGFRcys/eGFRcr-ratio and SGHS defined as eGFRcys/eGFRcr-ratio <0.7. Multivariable linear and logistic regression adjusted for demographic, metabolic, cardiovascular, and kidney covariates; sensitivity analyses used alternative eGFR equations. RESULTS:Mean eGFRcys/eGFRcr-ratio declined across glycemic categories (normoglycemia 0.95, prediabetes 0.90, diabetes 0.85; p < 0.001). SGHS prevalence increased stepwise (6.5%, 10.7%, and 19.5%, respectively). In fully adjusted models, higher HbA1c (per 10 mmol/mol) and fasting glucose (per 1 mmol/L) were inversely associated with the eGFRcys/eGFRcr-ratio (β -0.015 and -0.008, respectively; both p < 0.001) and positively associated with SGHS (odds ratio [OR] 1.27 and 1.12; both p < 0.001). Higher HOMA-IR was independently associated with SGHS, with the strongest associations observed in normoglycemia (OR 1.27, 95% confidence interval [CI] 1.12-1.45) and prediabetes (OR 1.41, 95% CI 1.12-1.76). CONCLUSIONS:Dysglycemia and insulin resistance were associated with a lower eGFRcys/eGFRcr-ratio and higher SGHS prevalence. These findings may reflect kidney vulnerability, altered biomarker metabolism, or both.

Patients with chronic kidney disease (CKD) have a high prevalence of cerebrovascular disease and cognitive impairment. The objective was to analyse whether plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated Tau231 (p-Tau231) are elevated in patients with CKD and to identify independent predictors of these biomarkers, with an emphasis on the role of measured glomerular filtration rate (mGFR). In this cross-sectional cohort study, we included 110 patients with CKD stages 3 and 4 (estimated GFR 15–59 ml/min/1.73 m2) without manifest cerebrovascular disease or dementia, and 55 healthy controls. Biomarkers of neurological disorders were measured with ultrasensitive single molecule array methods. Plasma concentrations (median [IQR]) of NfL (37.5 [22.1–47.5] vs. 13.4 [10.5–16.7] ng/L, p < 0.001), p-Tau231 (25.7 [19.1–38.7] vs. 13.9 [10.5–16.3] ng/L, p < 0.001) and GFAP (190 [140–281] vs. 153 [116–211] ng/L, p < 0.001) were elevated in patients with CKD vs. controls. Measured GFR was negatively correlated with NfL (r = − 0.706, p < 0.001), p-Tau231 (r = − 0.561, p < 0.001), and GFAP (r = − 0.385, p < 0.001). In multivariable linear regression models, mGFR was an independent predictor of log-transformed plasma concentrations of NfL (standardized beta coefficient [β] = − 0.439, p < 0.001) and GFAP (β = − 0.321, p < 0.001). Patients with CKD had elevated plasma concentrations of NfL, p-Tau231 and GFAP compared with controls, and these biomarkers were inversely correlated with mGFR. Measured GFR was a significant, independent predictor of plasma concentrations of NfL and GFAP in patients with CKD. The mechanisms underlying this association need further investigation. Plasma levels of NfL and GFAP should be interpreted cautiously in patients with marked reductions in GFR.

Abstract Background and Aims Patients with chronic kidney disease (CKD) have a high prevalence of cerebrovascular disease and cognitive impairment. The aim of the present study was to measure brain injury biomarkers in plasma in a cohort of patients with CKD stages 3 and 4, without a diagnosis of cerebrovascular disease, and to determine factors that independently predicted plasma levels of these biomarkers. Method This was a cross-sectional cohort study including 110 patients with CKD stages 3 and 4, and 55 healthy, matched, controls, recruited from the outpatient clinic at Sahlgrenska university hospital, Gothenburg, Sweden. None of the included study subjects had a diagnosis of cerebrovascular disease, cognitive impairment, or any other neurological disease. Plasma concentrations of neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated Tau (p-Tau231) were analyzed with ultrasensitive single molecule array (SIMOA). Measured GFR (mGFR) was determined by plasma clearance of ⁵¹Cr-EDTA. Values are medians [interquartile range]. For linear regression analyses standardised beta coefficients (β) are presented. Results Characteristics of CKD patients and healthy controls are presented in Table 1. Plasma concentrations of NfL (37.5 [22.1-47.5] vs. 13.4 [10.5-16.7] ng/L, p < 0.001), p-Tau231 (25.7 [19.1-38.7] vs. 13.9 [10.5-16.3] ng/L, p < 0.001) and GFAP (190 [140-281] vs. 153 [116-211] ng/L, p = 0.001) were significantly elevated in patients with CKD vs. controls. In CKD patients, mGFR showed statistically significant inverse correlations to plasma concentrations of NfL, p-Tau231, and GFAP (Table 2). In multiple regression analyses, mGFR was associated with plasma levels of NfL (β = −0.457, p < 0.001) and GFAP (β = −0.322, p < 0.001) independently of diabetes, age, troponin-T, b-hemoglobin, and aortic pulse-wave velocity. However, mGFR was not significantly associated with plasma levels of p-Tau231 in a multiple regression analysis. Conclusion Plasma levels of brain injury markers NfL, p-Tau231 and GFAP were elevated in patients with CKD stages 3 and 4, without a history of cerebrovascular disease, compared to healthy controls. Furthermore, mGFR independently predicted plasma concentrations of NfL and GFAP in multiple regression models. These results raise the possibility that reduced GFR per se may be associated with subclinical brain injury.

Abstract Background and Aims Cardiovascular disease is common in patients with chronic kidney disease (CKD). This may, at least in part, explain the high risk of mortality in this patient group. The aim of the present study was to identify factors associated with mortality in patients with CKD stages 3 and 4 without a diagnosis of heart disease. Method Study subjects were derived from a cohort of patients with CKD stages 3 and 4 who were recruited from our Nephrology Outpatient Clinic between February 2009 and December 2011. Ninety-one patients without a diagnosis of heart disease were included in this cross-sectional study. Mortality data were collected in April 2023. Results All-cause mortality was 28.6% (26 patients) during a mean follow-up of 11.2 ± 2.7 years. Comparison of baseline data between non-survivors and survivors showed that non-survivors were significantly older, had lower glomerular filtration rate (GFR), higher ambulatory systolic blood pressure (ASBP), less nocturnal dipping of ASBP, higher carotid–femoral pulse wave velocity (cfPWV) and higher serum levels of troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) [Tables 1 and 2]. In addition, the proportion of patients with diabetes and on treatment with beta-blockers was elevated in non-survivors [Tables 1 and 2]. There were no statistically significant differences between groups in smoking history, treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, diuretics, calcium channel blockers, alpha-blockers, statins, active vitamin D analogs, calcium-based or non-calcium-based phosphate binders. In a binary logistic regression analysis, to identify independent predictors of mortality, we included age, gender, baseline GFR, serum NT-proBNP, TnT, cfPWV, percent of nocturnal dipping of ASBP, diagnosis of diabetes, and treatment with beta-blockers. Only less nocturnal dipping of ASBP (Exp [β] value of 0.86, 95% CI 0.77–0.97, p = 0.016) and advancing age (Exp [β] value of 0.91, 95% CI 0.84–0.99, p = 0.024) significantly predicted all-cause mortality. Conclusion In patients with CKD stage 3 and 4 without a diagnosis of heart disease only older age and less nocturnal dipping of ASBP were independently associated with mortality. Although baseline levels of serum NT-proBNP and TnT were elevated in non-survivors, neither serum NT-proBNP nor TnT showed independent associations with mortality in this cohort.

Introduction IgA nephropathy (IgAN) is the most common glomerulonephritis globally. Because of the heterogeneity of the disease prognostic biomarkers are highly needed. Aim To investigate associations between galactose-deficient IgA1 (Gd-IgA1) concentrations in plasma and urine and disease activity and progression in patients with IgAN. Methods Serum and urine samples were collected at the time of kidney biopsy (baseline) in patients with IgAN (n = 40) and analysed for Gd-IgA1. Patients with chronic kidney disease (CKD) without IgAN (n = 21) and healthy controls (n = 19) were examined as controls. In 19 patients with IgAN, analyses of Gd-IgA1 were repeated after a median follow up time of approximately 10 years. Results Serum Gd-IgA1 and Gd-IgA1:IgA were significantly elevated at the time of kidney biopsy in patients with IgAN compared to patients with non-IgAN CKD and healthy controls (p < 0.001). Urinary Gd-IgA1:creatinine was significantly elevated in patients with IgAN compared to patients with non-IgAN CKD. Neither serum Gd-IgA1, nor serum Gd-IgA1:IgA, correlated significantly to estimated GFR, urine albumin:creatinine (UACR), or blood pressure, at baseline. Serum Gd-IgA1 and Gd-IgA1:IgA at time of biopsy did not correlate significantly to annual changes in eGFR or UACR during follow up. In patients with IgAN, serum Gd-IgA1 decreased significantly over time during approximately 10 years of follow up (Δ-20 ± 85%, p = 0.027). Urinary Gd-IgA1:creatinine showed a strong positive correlation to UACR in patients with IgAN and likely reflected unspecific glomerular barrier injury. Conclusion Although serum Gd-IgA1 and the Gd-IgA1:IgA ratio were significantly elevated in patients with IgAN at the time of kidney biopsy they were not related to disease activity or progression in this patient cohort.

Background and Aims In advanced stages of chronic kidney disease (CKD) some glucose-lowering agents, such as metformin, cannot be prescribed to patients with type 2 diabetes (T2D) due to the risk of accumulation and adverse events. Foods with bioactive components, “functional food”, can be an alternative to mitigate the metabolic disturbances in these patients. Previous research on experimental animals and patients with T2D has shown that sulforaphane, present in broccoli sprouts, improves insulin sensitivity and glucose control. We hypothesize that sulforaphane ingested as a broccoli sprout extract (BSE) can improve glucose control in patients with T2D and CKD. Method This is an ongoing multicentre randomized double-blinded controlled trial with glucose control as the primary outcome. Glucose control is evaluated by fasting serum glucose, serum insulin in all patients, and oral glucose tolerance test (OGTT) in patients not on insulin treatment. Moreover, as a secondary aim, we investigate the role of BSE in improving other signs of metabolic alterations, including oxidative stress, proteinuria, inflammation and production of uremic toxins from the gut microbiota. Patients: Adult patients with T2D and CKD (eGFR 15- 45 ml/min/1.73m2) are included and randomized 1:1 to receive BSE or placebo. Both groups are followed for 20 weeks. The first 12 weeks, patients receive BSE or placebo and are then followed for 8 weeks. Patients randomized to BSE receive an increasing dose of sulforaphane administered as BSE (Lantmännen®) starting with 50 µmmol/day in week 0 - 4; 100 µmmol/day in week 5 - 8 and 150 µmmol/day in week 9 - 12. The placebo consists of maltodextrin sprayed with copper-chlorophyllin. Blood and urine laboratory measurements and OGTT is performed at week 0, 12 and 20. Randomization is done using a computer-based block randomization algorithm. The protocol is registered at clinicaltrials.gov (NCT04858854). Results 98 patients with T2D and CKD from 12 centers in Sweden were included and the recruiting phase has now been finalized but the follow up phase is still ongoing. We here present baseline characteristics of all study participants (Table 1). Median age is 75 years and a minority are women. Mean eGFR corresponds to CKD stage 4 and there are large variations in albumin/creatinine ratios. Most participants are on a combination of oral glucose-lowering agents and insulin. A history of cardiovascular disease is common, and 21% had a previously had myocardial infarction. Conclusion We are currently conducting a randomized clinical trial testing if BSE can be used as an alternative or add-on to improve glucose control in patients with T2D and CKD stages 3-4 type and to see if this ‘high risk’ patient group could benefit from treatment with BSE.

Abstract Background and Aims In advanced stages of chronic kidney disease (CKD) some glucose-lowering agents, such as metformin, cannot be prescribed to patients with type 2 diabetes (T2D) due to the risk of accumulation and adverse events. Foods with bioactive components, “functional food”, can be an alternative to mitigate the metabolic disturbances in these patients. Previous research on experimental animals and patients with T2D has shown that sulforaphane, present in broccoli sprouts, improves insulin sensitivity and glucose control. We hypothesize that sulforaphane ingested as a broccoli sprout extract (BSE) can improve glucose control in patients with T2D and CKD. Method This is an ongoing multicentre randomized double-blinded controlled trial with glucose control as the primary outcome. Glucose control is evaluated by fasting serum glucose, serum insulin in all patients, and oral glucose tolerance test (OGTT) in patients not on insulin treatment. Moreover, as a secondary aim, we investigate the role of BSE in improving other signs of metabolic alterations, including oxidative stress, proteinuria, inflammation and production of uremic toxins from the gut microbiota. Patients: Adult patients with T2D and CKD (eGFR 15- 45 ml/min/1.73m2) are included and randomized 1:1 to receive BSE or placebo. Both groups are followed for 20 weeks. The first 12 weeks, patients receive BSE or placebo and are then followed for 8 weeks. Patients randomized to BSE receive an increasing dose of sulforaphane administered as BSE (Lantmännen®) starting with 50 µmmol/day in week 0 - 4; 100 µmmol/day in week 5 - 8 and 150 µmmol/day in week 9 - 12. The placebo consists of maltodextrin sprayed with copper-chlorophyllin. Blood and urine laboratory measurements and OGTT is performed at week 0, 12 and 20. Randomization is done using a computer-based block randomization algorithm. The protocol is registered at clinicaltrials.gov (NCT04858854). Results 98 patients with T2D and CKD from 12 centers in Sweden were included and the recruiting phase has now been finalized but the follow up phase is still ongoing. We here present baseline characteristics of all study participants (Table 1). Median age is 75 years and a minority are women. Mean eGFR corresponds to CKD stage 4 and there are large variations in albumin/creatinine ratios. Most participants are on a combination of oral glucose-lowering agents and insulin. A history of cardiovascular disease is common, and 21% had a previously had myocardial infarction. Conclusion We are currently conducting a randomized clinical trial testing if BSE can be used as an alternative or add-on to improve glucose control in patients with T2D and CKD stages 3-4 type and to see if this ‘high risk’ patient group could benefit from treatment with BSE.

Abstract Aims The overall aim was to identify sub‐clinical cardiac abnormalities by echocardiography in patients with chronic kidney disease (CKD) stages 3 and 4 and to investigate underlying mechanisms. Methods and results Ninety‐one patients with CKD stages 3 and 4, without a diagnosis of heart disease, and 41 healthy matched controls were included in this cross‐sectional study. Cardiac morphology and function were analysed with Doppler echocardiography and coronary flow velocity reserve (CFVR) in response to adenosine was measured in the left anterior descendent artery to detect coronary microvascular dysfunction (CMD). All study subjects had a left ventricular (LV) ejection fraction > 50%. Patients with CKD showed statistically significant increases in left atrial volume index and transmitral and pulmonary vein flow velocities during atrial contraction and prolonged LV isovolumetric relaxation time. Patients with CKD had significantly reduced CFVR vs. controls (2.74 ± 0.86 vs. 3.40 ± 0.89, P < 0.001), and 43% of patients were classified as having CMD compared with 9% of controls (P = 0.001). Conclusions Patients with CKD stages 3 and 4, without a diagnosis of heart disease, showed early abnormalities in LV diastolic function that did not fulfil the criteria for LV dysfunction according to current guidelines. A large proportion of CKD patients had CMD, suggesting that microvascular abnormalities may have a pathogenic role in the development of heart failure in this patient group.

Background/Aim: Calcifications of large arteries are frequent in chronic kidney disease (CKD) and may contribute to the high cardiovascular risk in this population. The aim of this study was to examine whether abdominal aortic calcification volume (AACV) was a predictor of the rate of decline in glomerular filtration rate (GFR) in a cohort of patients with CKD stages 3 and 4. Methods: Eighty-four patients with CKD stages 3 and 4 were enrolled in this prospective observational study. At study entry, and annually, GFR was measured by plasma 51Cr-EDTA clearance. At baseline, haemodynamics was assessed and AACV was determined by computer tomography. Results: The mean follow-up time was 3.4 years and mean decline in GFR was –2.69 mL/min/1.73 m2 per year. At baseline, abdominal aortic calcification (AAC) was detected in 66 patients (79%). A binary logistic regression analysis revealed that age was the only statistically significant independent predictor of AAC. In patients with AAC, male gender (B = 0.413, p = 0.030), aortic diastolic blood pressure (B = –0.025, p = 0.001) and ankle-brachial index (B = –1.666, p = 0.002) were independently associated with AACV using a multiple linear regression analysis. Neither the presence nor the extent of AAC was significantly associated with the rate of change in GFR during follow-up. Conclusion: In this cohort of patients with CKD stages 3 and 4, only age was an independent predictor of the presence of AAC. AACV was not associated with the rate of decline in GFR.

Background/Aims: Cardiovascular disease is the major cause of death in patients with chronic kidney disease (CKD). Rats with adenine-induced chronic renal failure (ACRF) develop severe renal insufficiency and metabolic abnormalities that closely resemble those in patients with uremia. The aim of the present study was to determine left ventricular (LV) morphology and function in rats with ACRF. Methods: Male Sprague-Dawley rats received either chow containing adenine or were pair-fed an identical diet without adenine (controls, C). After 9-13 weeks animals were anesthetized with isoflurane and cardiac function was assessed both by echocardiography and by LV catheterization. Results: Rats with ACRF showed increases in serum creatinine (323±107 vs. 33±5 µM, P< 0.05), mean arterial pressure (115±6 vs. 106±7 mmHg, P< 0.05) and LV weight (3.4±0.3 vs. 2.5±0.2 mg/kg, P< 0.05) vs. controls. Rats with ACRF had reduced early diastolic tissue Doppler velocities in the LV, enlarged left atrial diameter (4.8±0.8 vs. 3.5±0.4 mm, P< 0.05) and elevated LV end-diastolic pressure (15±5 vs. 8±1 mmHg, P< 0.01). Cardiac output was increased in ACRF rats (211±66 vs. 149±24 ml/min, P< 0.05) and systolic function preserved. In the LV of ACRF rats there were statistically significant (P< 0.05) increases in cardiomyocyte diameter, proliferation and apoptosis, while there was no difference between groups in fibrosis. Conclusion: Rats with ACRF develop LV hypertrophy and diastolic dysfunction while systolic performance was preserved. There was an increased hypertrophy and apoptosis of cardiomyocytes in the LV of ACRF rats. The cardiac abnormalities in ACRF rats resemble those in patients with CKD in which heart failure with preserved ejection fraction is common. Hence, this experimental model is well suited for studying pathophysiological mechanisms in chronic renocardiac syndromes.

Soluble guanylyl cyclase (sGC) is an effector enzyme of nitric oxide (NO). Recent work has unravelled how levels of this enzyme are controlled, and highlighted a role in vascular disease. We provide a timely summary of available knowledge on transcriptional regulation of sGC, including influences from the NOTCH signalling pathway and genetic variants. It is speculated that hypertension-induced repression of sGC starts a vicious circle that can be initiated by periods of stress, diet or genetic factors, and a key tenet is that reduction in sGC further raises blood pressure. The idea that dysregulation of sGC contributes to syndromes caused by defective NOTCH signalling is advanced, and we discuss drug repositioning for vascular disease prevention. The advantage of targeting sGC expression rather than activity is also considered. It is argued that transcriptional inputs on sGC arise from interactions with other cells, the extracellular matrix and microRNAs (miRNAs), and concluded that the promise of sGC as a target for prevention of cardiovascular disease has increased in recent time.

Aims: To examine the effects of 2 weeks of high-NaCl diet on left ventricular (LV) morphology and serum levels of cardiac troponin T (cTnT) in rats with adenine-induced chronic renal failure (ACRF). Methods: Male Sprague-Dawley rats either received chow containing adenine or were pair-fed an identical diet without adenine [controls (C)]. Approximately 10 weeks after the beginning of the study, the rats were randomized to either remain on a normal NaCl diet (NNa; 0.6%) or to be switched to high-NaCl chow (HNa; 4%) for 2 weeks, after which acute experiments were performed. Results: Rats with ACRF showed statistically significant increases (p < 0.001) in arterial pressure (AP), LV weight and fibrosis, and serum cTnT levels compared to controls. Two weeks of high-NaCl intake augmented the increases in AP, LV weight and fibrosis, and serum cTnT concentrations only in ACRF rats (p < 0.05 for group × NaCl intake interaction). Compared to group C-NNa, cTnT levels were elevated approximately 6-fold in group ACRF-NNa and 24-fold in group ACRF-HNa. Focal LV injury with cardiomyocyte necrosis, scarring, and fibrinoid necrosis of small arteries were only detected in group ACRF-HNa. There was a strong correlation between the degree of LV fibrosis and serum cTnT levels in ACRF rats (r = 0.81, p < 0.01). Conclusion: Two weeks of high-NaCl diet in rats with ACRF produces LV injury and aggravates increases in serum cTnT levels, presumably by causing hypertension-induced small artery lesions leading to myocardial ischemia. This model may be suitable for studying pathophysiological mechanisms in chronic renicardiac syndromes.

AIM:Rats with adenine-induced chronic renal failure (A-CRF) develop a reduced rate of relaxation of the thoracic aorta. The aim of this study was to elucidate the mechanisms underlying this abnormality.METHODS:Male Sprague Dawley rats received either chow containing adenine or were pair-fed with normal chow (controls). After 8-14 weeks, arterial function was analysed ex vivo using wire myography and the expression of proteins involved in vascular smooth muscle excitation-contraction coupling in the thoracic aorta was analysed.RESULTS:The rate of relaxation following washout of KCl was reduced in A-CRF rats vs. controls in the thoracic aorta (P < 0.01), abdominal aorta (P < 0.05), and common carotid artery (P < 0.05), but not in the common femoral artery. Relaxation rates of thoracic aortas increased (P < 0.01), but were not normalized, in response to washout of KCl with Ca2+ -free buffer. Microarray and qRT-PCR analyses of genes involved in excitation-contraction coupling identified 10 genes, which showed significantly altered expression in A-CRF thoracic aortas. At the protein level, the α2 subunit of the Na,K-ATPase (P < 0.001) and SERCA2 (P < 0.05) was significantly downregulated, whereas stromal interaction molecule 1 and calsequestrin-1 and calsequestrin-2 were significantly upregulated (P < 0.05).CONCLUSIONS:Rats with A-CRF show a marked alteration in relaxation of larger conduit arteries localized proximal to the common femoral artery. This abnormality may be caused by reduced cytosolic Ca2+ clearance in vascular smooth muscle cells secondary to dysregulation of proteins crucially involved in this process.

Rats with adenine‐induced chronic renal failure (ACRF) develop a reduced rate of relaxation, and increased stiffness of the aorta. The aim of this study was to investigate the effects of 2 weeks of high NaCl intake on vascular function in rats with ACRF.Male Sprague‐Dawley rats received either chow containing adenine (ACRF) or were pair‐fed a control diet (Controls, C). Two weeks prior to sacrifice animals were randomized to diet containing either normal salt (0.6% NaCl, NS) or high salt (4% NaCl, HS), resulting in four groups: C‐NS, C‐HS, ACRF‐NS and ACRF‐HS (n=11‐15 per group). Animals were sacrificed at 7‐10 weeks after study start and mesenteric arteries and thoracic aorta were analyzed with wire myograph.Animals with ACRF showed significant increases in serum creatinine and systolic blood pressure that was aggravated by high NaCl intake (138±14, 164±10, 152±7 and 202±14 mmHg in groups C‐NS, ACRF‐NS, C‐HS and ACRF‐HS, respectively). A decreased sensitivity to norepinephrine was found in mesenteric arteries of ACRF‐HS rats (P<0.05). In the thoracic aorta, the sensitivity to both sodium nitroprusside (SNP) and acetylcholine (ACh) were reduced only in ACRF‐HS animals (P<0.05). Furthermore, the ACRF‐HS group exhibited a marked decrease in aortic relaxation rate compared to ACRF‐NS animals (P<0.01).In rats with ACRF two weeks of high NaCl intake reduced the sensitivity to ACh and SNP in the thoracic aorta and aggravated the impairment in relaxation rate whereas vasodilator responses were unaffected in resistance arteries. These results indicate an abnormality in vascular smooth muscle function specifically in the thoracic aorta of ACRF animals that is augmented by high NaCl intake.

This study examined the effects of 2 wk of high-NaCl diet on kidney function and dynamic renal blood flow autoregulation (RBFA) in rats with adenine-induced chronic renal failure (ACRF). Male Sprague-Dawley rats received either chow containing adenine or were pair-fed an identical diet without adenine (controls). After 10 wk, rats were randomized to either remain on the same diet (0.6% NaCl) or to be switched to high 4% NaCl chow. Two weeks after randomization, renal clearance experiments were performed under isoflurane anesthesia and dynamic RBFA, baroreflex sensitivity (BRS), systolic arterial pressure variability (SAPV), and heart rate variability were assessed by spectral analytical techniques. Rats with ACRF showed marked reductions in glomerular filtration rate and renal blood flow (RBF), whereas mean arterial pressure and SAPV were significantly elevated. In addition, spontaneous BRS was reduced by ∼50% in ACRF animals. High-NaCl diet significantly increased transfer function fractional gain values between arterial pressure and RBF in the frequency range of the myogenic response (0.06-0.09 Hz) only in ACRF animals (0.3 ± 4.0 vs. -4.4 ± 3.8 dB; P < 0.05). Similarly, a high-NaCl diet significantly increased SAPV in the low-frequency range only in ACRF animals. To conclude, a 2-wk period of a high-NaCl diet in ACRF rats significantly impaired dynamic RBFA in the frequency range of the myogenic response and increased SAPV in the low-frequency range. These abnormalities may increase the susceptibility to hypertensive end-organ injury and progressive renal failure by facilitating pressure transmission to the microvasculature.