Reassuring pregnancy outcomes in women with mild COL4A3-5-related disease (Alport syndrome) and genetic type of disease can aid personalized counseling.

Individualized pre-pregnancy counseling and antenatal care for women with chronic kidney disease (CKD) require disease-specific data. Here, we investigated pregnancy outcomes and long-term kidney function in women with COL4A3-5 related disease (Alport Syndrome, (AS)) in a large multicenter cohort. The ALPART-network (mAternaL and fetal PregnAncy outcomes of women with AlpoRT syndrome), an international collaboration of 17 centers, retrospectively investigated COL4A3-5 related disease pregnancies after the 20th week. Outcomes were stratified per inheritance pattern (X-Linked AS (XLAS)), Autosomal Dominant AS (ADAS), or Autosomal Recessive AS (ARAS)). The influence of pregnancy on estimated glomerular filtration rate (eGFR)-slope was assessed in 192 pregnancies encompassing 116 women (121 with XLAS, 47 with ADAS, and 12 with ARAS). Median eGFR pre-pregnancy was over 90ml/min/1.73m2. Neonatal outcomes were favorable: 100% live births, median gestational age 39.0 weeks and mean birth weight 3135 grams. Gestational hypertension occurred during 23% of pregnancies (reference: 'general' CKD G1-G2 pregnancies incidence is 4-20%) and preeclampsia in 20%. The mean eGFR declined after pregnancy but remained within normal range (over 90ml/min/1.73m2). Pregnancy did not significantly affect eGFR-slope (pre-pregnancy ß=-1.030, post-pregnancy ß=-1.349). ARAS-pregnancies demonstrated less favorable outcomes (early preterm birth incidence 3/11 (27%)). ARAS was a significant independent predictor for lower birth weight and shorter duration of pregnancy, next to the classic predictors (pre-pregnancy kidney function, proteinuria, and chronic hypertension) though missing proteinuria values and the small ARAS-sample hindered analysis. This is the largest study to date on AS and pregnancy with reassuring results for mild AS, though inheritance patterns could be considered in counseling next to classic risk factors. Thus, our findings support personalized reproductive care and highlight the importance of investigating kidney disease-specific pregnancy outcomes.

Alkaline phosphatase treatment of acute kidney injury - an update.

Through improved insight in the increasing incidence and detrimental effects of acute kidney injury (AKI), its clinical relevance has become more and more apparent. Although treatment strategies for AKI have also somewhat improved, an adequate remedy still does not exist. Finding one is complicated by a multifactorial pathophysiology and by heterogeneity in the patient population. Alkaline phosphatase (AP) has been suggested as a therapy for sepsis-associated AKI because of its protective effects against lipopolysaccharide (LPS) induced inflammation and kidney injury in animals. However, translation of these protective effects into tangible clinical benefit has proven difficult. Because the anti-inflammatory properties of AP are likely not reliant on a direct effect on LPS itself, we postulate that other pathways are much more important in explaining the renoprotective properties ascribed to AP. The reevaluation of which properties of the AP enzyme are responsible for the benefit seen in the lab, is an important step to determine where the true potential of AP as a treatment strategy for AKI in the clinic lies. In this review, we will discuss how AP can prevent activation of harmful pro-inflammatory receptors, redirect cell-cell signaling, and protect barrier tissues, which together form the basis for current knowledge of the role of AP in the kidney. With this knowledge in mind and by analyzing currently available clinical evidence, we propose directions for new research that can determine whether AP as a treatment strategy for AKI has a future in the clinical field.

Potassium intake: the Cinderella electrolyte.

Dietary guidelines recommend intake targets for some essential minerals, based on observational and experimental evidence relating mineral intake levels to health outcomes. For prevention of cardiovascular disease, reducing sodium intake and increasing potassium intake are the principal tools. While reducing sodium intake has received greatest public health priority, emerging evidence suggests that increasing potassium intake may be a more important target for cardiovascular prevention. Increased potassium intake reduces blood pressure and mitigates the hypertensive effects of excess sodium intake, and the recent large Phase III SSaSS trial reported that increasing potassium intake (and reducing sodium intake) in populations with low potassium intake and high sodium intake, through salt substitution (25% KCl, 75%NaCl), reduces the risk of stroke in patients at increased cardiovascular risk. As key sources of potassium intake include fruit, vegetables, nuts, and legumes, higher potassium intake may be associated with healthy dietary patterns. The current review makes the case that increasing potassium intake might represent a more advantageous dietary strategy for prevention of cardiovascular disease. Future research should focus on addressing the independent effect of potassium supplementation in populations with low or moderate potassium intake, and determine effective strategies to increase potassium intake from diet.

The effect of liver surgery and fluid strategy on renin activity and aldosterone and anti-diuretic hormone levels: a secondary analysis of the GALILEO trial.

BACKGROUND: It is unknown whether liver surgery leads to increased RAAS activity and anti-diuretic hormone (ADH) levels and subsequent fluid accumulation. Furthermore, it is unknown whether the peri-operative fluid strategy changes this effect. METHODS: This is a pre-planned post hoc analysis of a randomised controlled trial which compared restrictive (n = 20) versus liberal fluid strategy (n = 20) in patients undergoing liver surgery. Primary outcomes for the current study were the difference in hormone levels after anaesthesia induction and after liver resection. Fluid overload was defined as a ≥10% increase in weight. RESULTS: Renin activity (6 [2.1-15.5] vs. 12 [4.6-33.5]) and ADH levels (6.0 [1.7-16.3] vs. 3.8 [1.6-14.7]) did not differ significantly before and after resection. However, aldosterone levels were significantly higher after resection (0.30 [0.17-0.49] vs. 0.69 [0.31-1.21] ). Renin activity and aldosterone levels did not differ between the groups. ADH was significantly higher in the restrictive strategy group (1.6 [1.1-2.1] vs 5.9 [3.8-16.0]). No differences in hormone levels were found in patients with and without fluid overload. DISCUSSION: Aldosterone levels increased after liver surgery but renin activity and ADH levels did not. ADH levels were higher in the restrictive group. Development of post-operative fluid overload was not associated with RAAS activity or ADH levels.

Assessment of renal sympathetic control using invasive pressure and flow velocity measurements in humans.

Renal sympathetic innervation is important in the control of renal and systemic hemodynamics and is a target for pharmacological and catheter-based therapies. The effect of a physiological sympathetic stimulus using static handgrip exercise on renal hemodynamics and intraglomerular pressure in humans is unknown. We recorded renal arterial pressure and flow velocity in patients with a clinical indication for coronary or peripheral angiography using a sensor-equipped guidewire during baseline, handgrip, rest, and hyperemia following intrarenal dopamine (30 µg/kg). Changes in perfusion pressure were expressed as the change in mean arterial pressure, and changes in flow were expressed as a percentage with respect to baseline. Intraglomerular pressure was estimated using a Windkessel model. A total of 18 patients (61% male and 39% female) with a median age of 57 yr (range: 27-85 yr) with successful measurements were included. During static handgrip, renal arterial pressure increased by 15.2 mmHg (range: 4.2-53.0 mmHg), whereas flow decreased by 11.2%, but with a large variation between individuals (range: -13.4 to 49.8). Intraglomerular pressure increased by 4.2 mmHg (range: -3.9 to 22.1 mmHg). Flow velocity under resting conditions remained stable, with a median of 100.6% (range: 82.3%-114.6%) compared with baseline. During hyperemia, maximal flow was 180% (range: 111%-281%), whereas intraglomerular pressure decreased by 9.6 mmHg (interquartile range: 4.8 to 13.9 mmHg). Changes in renal pressure and flow during handgrip exercise were significantly correlated (ρ = -0.68, P = 0.002). Measurement of renal arterial pressure and flow velocity during handgrip exercise allows the identification of patients with higher and lower sympathetic control of renal perfusion. This suggests that hemodynamic measurements may be useful to assess the response to therapeutic interventions aimed at altering renal sympathetic control.NEW & NOTEWORTHY Renal sympathetic innervation is important in the homeostasis of systemic and renal hemodynamics. We showed that renal arterial pressure significantly increased and that flow decreased during static handgrip exercise using direct renal arterial pressure and flow measurements in humans, but with a large difference between individuals. These findings may be useful for future studies aimed to assess the effect of interventions that influence renal sympathetic control.

Salt-sensitive trait of normotensive individuals is associated with altered autonomous cardiac regulation: a randomized controlled intervention study.

Blood pressure (BP) responses to sodium intake show great variation, discriminating salt-sensitive (SS) from salt-resistant (SR) individuals. The pathophysiology behind salt sensitivity is still not fully elucidated. We aimed to investigate salt-induced effects on body fluid, vascular tone, and autonomic cardiac response with regard to BP change in healthy normotensive individuals. We performed a randomized crossover study in 51 normotensive individuals with normal body mass index and estimated glomerular filtration rate. Subjects followed both a low-Na+ diet (LSD, <50 mmol/day) and a high-Na+ diet (HSD, >200 mmol/day). Cardiac output, systemic vascular resistance (SVR), and cardiac autonomous activity, through heart rate variability and cross-correlation baroreflex sensitivity (xBRS), were assessed with noninvasive continuous finger BP measurements. In a subset, extracellular volume (ECV) was assessed by iohexol measurements. Subjects were characterized as SS if mean arterial pressure (MAP) increased ≥3 mmHg after HSD. After HSD, SS subjects (25%) showed a 6.1-mmHg (SD 1.9) increase in MAP. No differences between SS and SR in body weight, cardiac output, or ECV were found. SVR was positively correlated with Delta BP (r = 0.31, P = 0.03). xBRS and heart rate variability were significantly higher in SS participants compared to SR participants after both HSD and LSD. Sodium loading did not alter heart rate variability within groups. Salt sensitivity in normotensive individuals is associated with an inability to decrease SVR upon high salt intake that is accompanied by alterations in autonomous cardiac regulation, as reflected by decreased xBRS and heart rate variability. No discriminatory changes upon high salt were observed among salt-sensitive individuals in body weight and ECV.NEW & NOTEWORTHY Extracellular fluid expansion in normotensive individuals after salt loading is present in both salt-sensitive and salt-resistant individuals and is not discriminatory to the blood pressure response to sodium loading in a steady-state measurement. In normotensive subjects, the ability to sufficiently vasodilate seems to play a pivotal role in salt sensitivity. In a normotensive cohort, differences in sympathovagal balance are also present in low-salt conditions rather than being affected by salt loading. Whereas treatment and prevention of salt-sensitive blood pressure increase are mostly focused on renal sodium handling and extracellular volume regulation, our study suggests that an inability to adequately vasodilate and altered autonomous cardiac functioning are additional key players in the pathophysiology of salt-sensitive blood pressure increase.

Novel mechanisms of salt-sensitive hypertension.

A high dietary sodium-consumption level is considered the most important lifestyle factor that can be modified to help prevent an increase in blood pressure and the development of hypertension. Despite numerous studies over the past decades, the pathophysiology explaining why some people show a salt-sensitive blood pressure response and others do not is incompletely understood. Here, a brief overview of the latest mechanistic insights is provided, focusing on the mononuclear phagocytic system and inflammation, the gut-kidney axis, and epigenetics. The article also discusses the effects of 3 types of novel drugs on salt-sensitive hypertension-sodium-glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors. The conclusion is that besides kidney-centered mechanisms, vasoconstrictor mechanisms are also relevant for both the understanding and treatment of this blood pressure phenotype.

Low Urinary Potassium Excretion Is Associated with Higher Risk of All-Cause Mortality in Patients with Type 2 Diabetes: Results of the Dutch Diabetes and Lifestyle Cohort Twente (DIALECT).

BACKGROUND: Low 24-h urinary potassium excretion, reflecting low potassium intake, is associated with premature mortality in the general population. OBJECTIVES: To determine whether urinary potassium excretion is associated with all-cause mortality in patients with type 2 diabetes. METHODS: We performed a prospective cohort study in 654 patients with type 2 diabetes in the Diabetes and Lifestyle Cohort Twente (DIALECT). Sex-specific tertiles of 24-h urinary potassium excretion were analyzed in a multivariable Cox regression model with all-cause mortality. The outpatient program of the hospital uses a continuous surveillance system by the municipal registry of death to ensure up-to-date information on the patient's status (alive or deceased). FFQs were used to study associations between urinary potassium excretion and food products. RESULTS: Urinary potassium excretion at baseline was 84 ± 25 mmol/d in males and 65 ± 22 mmol/d in females, corresponding to estimated potassium intakes of 4250 ± 1270 mg/d and 3300 ± 875 mg/d. During a median follow-up of 5.2 (IQR: 2.7-7.9] y, 96 participants died. In a fully adjusted model, patients in the lowest sex-specific tertile had a higher risk of all-cause mortality, compared with patients in the highest sex-specific tertile (HR: 2.09; 95% CI: 1.06, 4.10; P = 0.03). Patients in the lowest sex-specific tertile consumed fewer fruits and vegetables, dairy, coffee, and potato products compared with patients in the highest sex-specific tertile (all P < 0.05). CONCLUSIONS: Low potassium intake is associated with a higher risk of all-cause mortality in Dutch patients with type 2 diabetes. Intervention studies are needed to determine whether potassium supplementation improves longevity in patients with type 2 diabetes. This trial was registered in the Dutch Trial Register as NTR trial code 5855.

Chronic kidney disease increases the susceptibility to negative effects of low and high potassium intake.

BACKGROUND AND HYPOTHESIS: Dietary potassium (K+) has emerged as a modifiable factor for cardiovascular and kidney health in the general population, but its role in people with chronic kidney disease (CKD) is unclear. Here, we hypothesize that CKD increases the susceptibility to negative effects of low and high K+ diets. METHODS: We compared the effects of low, normal, or high KChloride (KCl) diets and a high KCitrate diet for four weeks in male rats with normal kidney function and in male rats with CKD using the 5/6th nephrectomy model (5/6Nx). RESULTS: Compared to rats with normal kidney function, 5/6Nx rats on the low KCl diet developed more severe extracellular and intracellular hypokalemia and more severe kidney injury, characterized by nephromegaly, infiltration of T-cells and macrophages, decreased eGFR and increased albuminuria. The high KCl diet caused hyperkalemia, hyperaldosteronism, hyperchloremic metabolic acidosis and severe hypertension in 5/6Nx but not in sham rats. The high KCitrate diet caused hypochloremic metabolic alkalosis but attenuated hypertension despite higher abundance of the phosphorylated sodium chloride cotransporter (pNCC) and similar levels of plasma aldosterone and epithelial sodium channel (ENaC) abundance. All 5/6Nx groups had more collagen deposition than the sham groups and this effect was most pronounced in the high KCitrate group. Plasma aldosterone correlated strongly with kidney collagen deposition. CONCLUSIONS: CKD increases the susceptibility to negative effects of low and high K+ diets in male rats, although the injury patterns are different. The low K+ diet caused inflammation, nephromegaly and kidney function decline, whereas the high K+ diet caused hypertension, hyperaldosteronism and kidney fibrosis. High KCitrate attenuated the hypertensive but not the pro-fibrotic effect of high KCl, which may be attributable to K+-induced aldosterone secretion. Our data suggest that especially in people with CKD it is important to identify the optimal threshold of dietary K+ intake.

Alkaline phosphatase to treat ischaemia-reperfusion injury in living-donor kidney transplantation: APhIRI I feasibility pilot study.

AIMS: Ischemia-reperfusion injury (IRI) during kidney transplant procedures is associated with adverse outcome. Alkaline phosphatase (AP) is an enzyme that has the potential to dampen IRI. Prior to this study, it had not been tested in the setting of kidney transplantation. This study aimed to evaluate the safety and feasibility of peri-procedural AP administration in living donor kidney transplantation. METHODS: In this double blind, randomized, placebo-controlled, single-center pilot study, all eligible recipients of living donor kidneys were asked to give informed consent. AP (bRESCAP) or a placebo was administered intravenously over 24 hours after the transplantation procedure. The primary outcome-graft function at 1 year-was represented by iohexol measured glomerular filtration rate (mGFR). Serum and urine biomarkers within seven days after surgery were used as surrogate markers of kidney function and injury. RESULTS: Eleven patients were enrolled of whom five were treated with bRESCAP and six with placebo. After 1 year, mGFR was not different between groups. No specific adverse events were observed in the bRESCAP group. Urine expression of injury biomarkers CCL14, NGAL and Cystatin C was lower in the bRESCAP group at day seven. This was statistically significant. CONCLUSION: This study illustrates that bRESCAP treatment is feasible in kidney transplantation, might have a dampening effect on IRI induced renal inflammation, and raises no safety concerns. Future research will evaluate the effects of bRESCAP treatment in donation after circulatory death kidney transplantation where IRI is more pronounced.

Self-Monitoring and Self-Efficacy in Patients with Chronic Kidney Disease During Low-Sodium Diet Self-Management Interventions: Secondary Analysis of the ESMO and SUBLIME Trials.

BACKGROUND: Patients with chronic kidney disease are often requested to engage in self-monitoring sodium (i.e. salt) intake, but it is currently unknown how self-monitoring would empower them. This study aims to assess: (1) how frequent self-monitoring tools are being used during low-sodium diet self-management interventions; (2) whether self-efficacy (i.e. trust in own capability to manage the chronic disease) is associated with self-monitoring frequency; and (3) whether higher self-monitoring frequency is associated with an improvement in self-efficacy over time. METHOD: Data from two multicenter randomized controlled trials (ESMO [n = 151] and SUBLIME [n = 99]) among adult Dutch patients with chronic kidney disease (eGFR ≥ 20-25 mL/min/1.73 m2) were used. In both studies, routine care was compared to a 3-month low-sodium diet self-management intervention with several self-monitoring tools (online food diary, home blood pressure monitor, and urinary sodium measurement device [only ESMO]). Data was collected on usage frequency of self-monitoring tools. Frequencies during the interventions were compared between low and high baseline self-efficacy groups using the Mann-Whitney U test and T-test and associated with changes in self-efficacy during the interventions using Spearman correlation coefficients. RESULTS: Large variations in self-monitoring frequency were observed. In both interventions, usage of self-monitoring tools was highest during the first month with sharp drops thereafter. The online food diary was the most frequently used tool. In the ESMO intervention, low baseline self-efficacy was associated with a higher usage frequency of self-monitoring tools. This finding was not confirmed in the SUBLIME intervention. No significant associations were found between usage frequency of self-monitoring tools and changes in self-efficacy over time. CONCLUSION: Patients with low self-efficacy might benefit most from frequent usage of self-monitoring tools when sufficient guidance and support is provided.

Effects of Short-Term Potassium Chloride Supplementation in Patients with CKD.

BACKGROUND: Observational studies suggest that adequate dietary potassium intake (90-120 mmol/day) may be renoprotective, but the effects of increasing dietary potassium and the risk of hyperkalemia are unknown. METHODS: This is a prespecified analysis of the run-in phase of a clinical trial in which 191 patients (age 68±11 years, 74% males, 86% European ancestry, eGFR 31±9 ml/min per 1.73 m2, 83% renin-angiotensin system inhibitors, 38% diabetes) were treated with 40 mmol potassium chloride (KCl) per day for 2 weeks. RESULTS: KCl supplementation significantly increased urinary potassium excretion (72±24 to 107±29 mmol/day), plasma potassium (4.3±0.5 to 4.7±0.6 mmol/L), and plasma aldosterone (281 [198-431] to 351 [241-494] ng/L), but had no significant effect on urinary sodium excretion, plasma renin, BP, eGFR, or albuminuria. Furthermore, KCl supplementation increased plasma chloride (104±3 to 105±4 mmol/L) and reduced plasma bicarbonate (24.5±3.4 to 23.7±3.5 mmol/L) and urine pH (all P<0.001), but did not change urinary ammonium excretion. In total, 21 participants (11%) developed hyperkalemia (plasma potassium 5.9±0.4 mmol/L). They were older and had higher baseline plasma potassium. CONCLUSIONS: In patients with CKD stage G3b-4, increasing dietary potassium intake to recommended levels with potassium chloride supplementation raises plasma potassium by 0.4 mmol/L. This may result in hyperkalemia in older patients or those with higher baseline plasma potassium. Longer-term studies should address whether cardiorenal protection outweighs the risk of hyperkalemia.Clinical trial number: NCT03253172.

Sex-specific associations between potassium intake, blood pressure, and cardiovascular outcomes: the EPIC-Norfolk study.

AIMS: A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown. METHODS AND RESULTS: An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex]. CONCLUSION: The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP.

Perturbation of Copper Homeostasis Sensitizes Cancer Cells to Elevated Temperature.

Temporary elevation of tumor temperature, also known as hyperthermia, is a safe and well-tolerated treatment modality. The efficacy of hyperthermia can be improved by efficient thermosensitizers, and various candidate drugs, including inhibitors of the heat stress response, have been explored in vitro and in animal models, but clinically relevant thermosensitizers are lacking. Here, we employ unbiased in silico approaches to uncover new mechanisms and compounds that could be leveraged to increase the thermosensitivity of cancer cells. We then focus on elesclomol, a well-performing compound, which amplifies cell killing by hyperthermia by 5- to 20-fold in cell lines and outperforms clinically applied chemotherapy when combined with hyperthermia in vitro. Surprisingly, our findings suggest that the thermosensitizing effects of elesclomol are independent of its previously reported modes of action but depend on copper shuttling. Importantly, we show that, like elesclomol, multiple other copper shuttlers can thermosensitize, suggesting that disturbing copper homeostasis could be a general strategy for improving the efficacy of hyperthermia.

Recovery of dialysis patients with COVID-19: health outcomes 3 months after diagnosis in ERACODA.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-related short-term mortality is high in dialysis patients, but longer-term outcomes are largely unknown. We therefore assessed patient recovery in a large cohort of dialysis patients 3 months after their COVID-19 diagnosis. METHODS: We analyzed data on dialysis patients diagnosed with COVID-19 from 1 February 2020 to 31 March 2021 from the European Renal Association COVID-19 Database (ERACODA). The outcomes studied were patient survival, residence and functional and mental health status (estimated by their treating physician) 3 months after COVID-19 diagnosis. Complete follow-up data were available for 854 surviving patients. Patient characteristics associated with recovery were analyzed using logistic regression. RESULTS: In 2449 hemodialysis patients (mean ± SD age 67.5 ± 14.4 years, 62% male), survival probabilities at 3 months after COVID-19 diagnosis were 90% for nonhospitalized patients (n = 1087), 73% for patients admitted to the hospital but not to an intensive care unit (ICU) (n = 1165) and 40% for those admitted to an ICU (n = 197). Patient survival hardly decreased between 28 days and 3 months after COVID-19 diagnosis. At 3 months, 87% functioned at their pre-existent functional and 94% at their pre-existent mental level. Only few of the surviving patients were still admitted to the hospital (0.8-6.3%) or a nursing home (∼5%). A higher age and frailty score at presentation and ICU admission were associated with worse functional outcome. CONCLUSIONS: Mortality between 28 days and 3 months after COVID-19 diagnosis was low and the majority of patients who survived COVID-19 recovered to their pre-existent functional and mental health level at 3 months after diagnosis.

Distinct osmoregulatory responses to sodium loading in patients with altered glycosaminoglycan structure: a randomized cross-over trial.

BACKGROUND: By binding to negatively charged polysaccharides called glycosaminoglycans, sodium can be stored in the body-particularly in the skin-without concurrent water retention. Concordantly, individuals with changed glycosaminoglycan structure (e.g. type 1 diabetes (DM1) and hereditary multiple exostosis (HME) patients) may have altered sodium and water homeostasis. METHODS: We investigated responses to acute (30-min infusion) and chronic (1-week diet) sodium loading in 8 DM1 patients and 7 HME patients in comparison to 12 healthy controls. Blood samples, urine samples, and skin biopsies were taken to investigate glycosaminoglycan sulfation patterns and both systemic and cellular osmoregulatory responses. RESULTS: Hypertonic sodium infusion increased plasma sodium in all groups, but more in DM1 patients than in controls. High sodium diet increased expression of nuclear factor of activated t-cells 5 (NFAT5)-a transcription factor responsive to changes in osmolarity-and moderately sulfated heparan sulfate in skin of healthy controls. In HME patients, skin dermatan sulfate, rather than heparan sulfate, increased in response to high sodium diet, while in DM1 patients, no changes were observed. CONCLUSION: DM1 and HME patients show distinct osmoregulatory responses to sodium loading when comparing to controls with indications for reduced sodium storage capacity in DM1 patients, suggesting that intact glycosaminoglycan biosynthesis is important in sodium and water homeostasis. Trial registration These trials were registered with the Netherlands trial register with registration numbers: NTR4095 ( https://www.trialregister.nl/trial/3933 at 2013-07-29) and NTR4788 ( https://www.trialregister.nl/trial/4645 at 2014-09-12).

Blood pressure monitoring in kidney transplantation: a systematic review on hypertension and target organ damage.

BACKGROUND: Sparse studies show that ambulatory blood pressure monitoring (ABPM) is superior to office BP (oBP) measurements to predict target organ damage and cardiovascular (CV) events in kidney transplant recipients (KTRs). We performed a systematic review aimed at determining the potential associations between BP recordings by different methods and renal and CV outcomes in this population. METHODS: Major medical databases were searched for studies enrolling adult KTRs undergoing 24h ABPM compared to office or home BP measurements. Main outcomes were: associations between different BP recordings and renal and CV outcomes. Additionally, any association between the circadian BP pattern (dipping/non-dipping status) and outcomes was assessed. RESULTS: Twenty-two studies (2078 participants) were reviewed. Amongst 12 studies collecting data on renal endpoints, ten studies found that BP assessed by ABPM was a stronger predictor of renal function decline, assessed by serum creatinine (SCr) and/or creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR), than traditional office measurements. Twelve studies analyzed the relation between different BP recordings and CV target organ damages and reported robust correlations between echocardiographic abnormalities [i.e. left ventricular mass index (LVM/LVMI)] and 24h ABPM, but not with office BPs. Furthermore, 24h ABPM correlated better than oBP with markers of vascular damage, such as carotid intima-media thickness (IMT), diffuse thickening, and endothelial dysfunction. Additionally, abnormal circadian BP pattern (non-dippers and reverse dippers) identified a group of kidney recipients at risk for kidney function loss and CV abnormalities. CONCLUSIONS: In our systematic review, ABPM reflected target organ damage more closely than oBP in KTRs. Furthermore, altered circadian BP profile associated with renal and CV target organ damages.

Estimation of Intraglomerular Pressure Using Invasive Renal Arterial Pressure and Flow Velocity Measurements in Humans.

BACKGROUND: Glomerular hyperfiltration resulting from an elevated intraglomerular pressure (Pglom) is an important cause of CKD, but there is no feasible method to directly assess Pglom in humans. We developed a model to estimate Pglom in patients from combined renal arterial pressure and flow measurements. METHODS: We performed hemodynamic measurements in 34 patients undergoing renal or cardiac angiography under baseline conditions and during hyperemia induced by intrarenal dopamine infusion (30 µg/kg). For each participant during baseline and hyperemia, we fitted an adapted three-element Windkessel model that consisted of characteristic impedance, compliance, afferent resistance, and Pglom. RESULTS: We successfully analyzed data from 28 (82%) patients. Median age was 58 years (IQR, 52-65), median eGFR was 95 ml/min per 1.73 m2 (IQR, 74-100) using the CKD-EPI formula, 30% had microalbuminuria, and 32% had diabetes. The model showed a mean Pglom of 48.0 mm Hg (SD=10.1) at baseline. Under hyperemia, flow increased by 88% (95% CI, 68% to 111%). This resulted in a 165% (95% CI, 79% to 294%) increase in afferent compliance and a 13.1-mm Hg (95% CI, 10.0 to 16.3) decrease in Pglom. In multiple linear regression analysis, diabetes (coefficient, 10.1; 95% CI, 5.1 to 15.1), BMI (0.99 per kg/m2; 95% CI, 0.38 to 1.59), and renal perfusion pressure (0.42 per mm Hg; 95% CI, 0.25 to 0.59) were significantly positively associated with baseline Pglom. CONCLUSIONS: We constructed a model on the basis of proximal renal arterial pressure and flow velocity measurements that provides an overall estimate of glomerular pressure and afferent and efferent resistance in humans. The model provides a novel research technique to evaluate the hemodynamics of CKD on the basis of direct pressure and flow measurements. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Functional HEmodynamics in patients with and without Renal Artery stenosis (HERA), NL40795.018.12 at the Dutch national trial registry (toetsingonline.nl).

Associations between gut microbiota, faecal short-chain fatty acids, and blood pressure across ethnic groups: the HELIUS study.

AIMS: Preliminary evidence from animal and human studies shows that gut microbiota composition and levels of microbiota-derived metabolites, including short-chain fatty acids (SCFAs), are associated with blood pressure (BP). We hypothesized that faecal microbiota composition and derived metabolites may be differently associated with BP across ethnic groups. METHODS AND RESULTS: We included 4672 subjects (mean age 49.8 ± 11.7 years, 52% women) from six different ethnic groups participating in the HEalthy Life In an Urban Setting (HELIUS) study. The gut microbiota was profiled using 16S rRNA gene amplicon sequencing. Associations between microbiota composition and office BP were assessed using machine learning prediction models. In the subgroups with the largest associations, faecal SCFA levels were compared in 200 subjects with lower or higher systolic BP. Faecal microbiota composition explained 4.4% of the total systolic BP variance. Best predictors for systolic BP included Roseburia spp., Clostridium spp., Romboutsia spp., and Ruminococcaceae spp. Explained variance of the microbiota composition was highest in Dutch subjects (4.8%), but very low in South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan and Turkish descent groups (explained variance <0.8%). Faecal SCFA levels, including acetate (P < 0.05) and propionate (P < 0.01), were lower in young Dutch participants with low systolic BP. CONCLUSIONS: Faecal microbiota composition is associated with BP, but with strongly divergent associations between ethnic groups. Intriguingly, while Dutch participants with lower BP had higher abundances of several SCFA-producing microbes, they had lower faecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP.