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Background and Hypothesis: Kidney macrophage infiltration is a histological hallmark of vasculitic lesions and is strongly linked to disease activity in anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AGN). The precise mechanisms by which kidney macrophages influence local inflammation and long-term damage remain largely unknown., Methods: Here, we investigate kidney macrophage diversity using single-cell transcriptome analysis of 25 485 freshly retrieved unfrozen, high-quality kidney CD45+ immune cells from five AGN patients during active disease, a lupus nephritis and nephrectomy control. Detailed subclustering of myeloid cells was performed to identify disease-specific macrophage subtypes. Next, transcriptome differences between macrophage subsets and disease serotypes were assessed. Findings were validated by immunostainings of an extended cohort of kidney biopsies and flow cytometric analysis of peripheral blood monocytes., Results: Four main macrophage subsets were identified, including a classical monocyte-derived macrophage (MDM) subset expressing a chemotactic (CXCL2, CXCL3, CXCL8, CCL3) and pro-inflammatory (IL1β, TNF) set of markers and a osteopontin/SPP1+ lipid-associated macrophage (SPP1 LAMs) subtype exhibiting distinctive upregulation of fibrotic genesets. AGN samples revealed a markedly increased proportion of CD163+ macrophages, predominantly composed of classical MDMs, accompanied by resident-like C1Q macrophages, and SPP1 LAMs An analogous trend was observed in the expansion of peripheral blood classical monocytes during active disease. The proteinase 3 (PR3)-AGN subtype exhibited heightened classical MDM and SPP1 LAM infiltration and markers of acute inflammation, while interferon signaling and markers of chronicity were reduced compared to myeloperoxidase (MPO)-AGN., Conclusions: Our findings highlight the expression of inflammatory and fibrotic genes by kidney macrophage subsets in AGN. Classical monocyte dysregulation might contribute to inflammation in the pathogenesis of AGN. Targeting these specific monocyte/macrophage subsets may potentially control the inflammatory cascade and attenuate resulting fibrosis in AGN and kidney disease in general., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background and Hypothesis: Chronic kidney disease (CKD) remains unexplained in at least 20% of patients. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, but prospective data from routine clinical practice are limited. We aimed to determine the diagnostic yield and relevance of MPS-based gene panel testing in patients with unexplained CKD in a real-world context. We additionally examined barriers to implementation of genetic testing., Methods: In this prospective cohort study, we recruited patients with unexplained CKD (eGFR <60mL/min/1.73 m2 without underlying clinical diagnosis) with onset <50 years who underwent MPS-based multi-gene panel testing from 11 academic and non-academic hospitals across the Netherlands. In patients with a (likely) pathogenic variant, we verified that the variant likely explained the clinical phenotype. A nationwide online survey was sent out to all Dutch nephrologists and residents to investigate potential barriers for gene panel testing., Results: A diagnostic variant was identified in 59/340 participants (17%). Most common diagnostic variants were in NPHP1 (13 patients), COL4A3 (12 patients), COL4A4 (5 patients), COL4A5 (6 patients), and PAX2 (5 patients). A genetic diagnosis led to at least one clinical consequence in 73% of patients. Main barriers reported by Dutch nephrologists (N=71) included genetic illiteracy (53%), difficulties with test selection (51%), and lack of time (43%)., Conclusion: MPS-based multi-gene panel testing yielded a genetic diagnosis in 17% of patients with unexplained CKD. Our findings support the relevance of MPS in the diagnostic workup of adults with unexplained CKD with onset <50 years. Additionally, our results underline the need to improve genetic education among nephrologists to better the implementation of MPS-based diagnostic testing in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Through improved insights into 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 (ALP) 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, its effectiveness as an AKI treatment has not been demonstrated definitively. Because the anti-inflammatory properties of ALP 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 ALP. The re-evaluation of which properties of the ALP enzyme are responsible for the benefit seen in the lab is an important step in determining where the true potential of ALP as a treatment strategy for AKI in the clinic lies. In this review we will discuss how ALP can prevent activation of harmful pro-inflammatory receptors, redirect cell-cell signalling and protect barrier tissues, which together form the basis for current knowledge of the role of ALP in the kidney. With this knowledge in mind and by analysing currently available clinical evidence, we propose directions for new research that can determine whether ALP as a treatment strategy for AKI has a future in the clinical field., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: 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 the negative effects of low and high K+ diets., Methods: We compared the effects of low, normal and high KChloride (KCl) diets and a high KCitrate diet for 4 weeks in male rats with normal kidney function and in male rats with CKD using the 5/6th nephrectomy model (5/6Nx)., Results: Compared with rats with normal kidney function, 5/6Nx rats on the low KCl diet developed more severe extracellular and intracellular K+ depletion and more severe kidney injury, characterized by nephromegaly, infiltration of T cells and macrophages, decreased estimated glomerular filtration rate 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 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

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 Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The spectacular radiation of insects has produced a stunning diversity of phenotypes. During the past 250 years, research on insect systematics has generated hundreds of terms for naming and comparing them. In its current form, this terminological diversity is presented in natural language and lacks formalization, which prohibits computer-assisted comparison using semantic web technologies. Here we propose a Model for Describing Cuticular Anatomical Structures (MoDCAS) which incorporates structural properties and positional relationships for standardized, consistent, and reproducible descriptions of arthropod phenotypes. We applied the MoDCAS framework in creating the ontology for the Anatomy of the Insect Skeleto-Muscular system (AISM). The AISM is the first general insect ontology that aims to cover all taxa by providing generalized, fully logical, and queryable, definitions for each term. It was built using the Ontology Development Kit (ODK), which maximizes interoperability with Uberon (Uberon multispecies anatomy ontology) and other basic ontologies, enhancing the integration of insect anatomy into the broader biological sciences. A template system for adding new terms, extending, and linking the AISM to additional anatomical, phenotypic, genetic, and chemical ontologies is also introduced. The AISM is proposed as the backbone for taxon-specific insect ontologies and has potential applications spanning systematic biology and biodiversity informatics, allowing users to: 1) use controlled vocabularies and create semiautomated computer-parsable insect morphological descriptions; 2) integrate insect morphology into broader fields of research, including ontology-informed phylogenetic methods, logical homology hypothesis testing, evo-devo studies, and genotype to phenotype mapping; and 3) automate the extraction of morphological data from the literature, enabling the generation of large-scale phenomic data, by facilitating the production and testing of informatic tools able to extract, link, annotate, and process morphological data. This descriptive model and its ontological applications will allow for clear and semantically interoperable integration of arthropod phenotypes in biodiversity studies., (© The Author(s) 2023. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: SARS-CoV-2 vaccines are effective at reducing symptomatic and asymptomatic COVID-19. Limited studies have compared symptoms, threshold cycle (Ct) values from reverse transcription (RT)-PCR testing, and serological testing results between previously vaccinated vs unvaccinated populations with SARS-CoV-2 infection., Methods: Healthcare personnel (HCP) with a positive SARS-CoV-2 RT-PCR test within the previous 14 to 28 days completed surveys including questions about demographics, medical conditions, social factors, and symptoms of COVID-19. Ct values were observed, and serological testing was performed for anti-nucleocapsid (anti-N) and anti-Spike (anti-S) antibodies at enrollment and 40 to 90 days later. Serological results were compared to HCP with no known SARS-CoV-2 infection and negative anti-N testing., Results: There were 104 unvaccinated/not fully vaccinated and 77 vaccinated HCP with 2 doses of an mRNA vaccine at time of infection. No differences in type or duration of symptoms were reported (P = 0.45). The median (interquartile range [IQR]) Ct was 21.4 (17.6-24.6) and 21.5 (18.1-24.6) for the unvaccinated and vaccinated HCP, respectively. Higher anti-N IgG was observed in unvaccinated HCP (5.08 S/CO, 3.08-6.92) than vaccinated (3.61 signal to cutoff ratio [S/CO], 2.16-5.05). Anti-S IgG was highest among vaccinated HCP with infection (34 285 aribitrary units [AU]/mL, 17 672-61 775), followed by vaccinated HCP with no prior infection (1452 AU/mL, 791-2943), then unvaccinated HCP with infection (829 AU/mL, 290-1555). Anti-S IgG decreased 1.56% (0.9%-1.79%) per day in unvaccinated and 0.38% (0.03%-0.94%) in vaccinated HCP., Conclusions: Vaccinated HCP infected with SARS-CoV-2 reported comparable symptoms and had similar Ct values relative to unvaccinated. However, vaccinated HCP had increased and prolonged anti-S and decreased anti-N response relative to unvaccinated., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The cause of chronic kidney disease (CKD) remains unknown in ∼20% of patients with kidney failure. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, with a diagnostic yield of 12%-56%. Here, we report the use of MPS to establish a genetic diagnosis in a 24-year-old index patient who presented with hypertension, nephrotic-range proteinuria and kidney failure of unknown origin. Additionally, we describe a second family with the same mutation presenting with early-onset CKD., Results: In Family 1, MPS identified a known pathogenic variant in GLA (p.Ile319Thr), and plasma globotriaosylsphingosine and α-galactosidase A activity were compatible with the diagnosis of Fabry disease (FD). Segregation analysis identified three other family members carrying the same pathogenic variant who had mild or absent kidney phenotypes. One family member was offered enzyme therapy. While FD could not be established with certainty as the cause of kidney failure in the index patient, no alternative explanation was found. In Family 2, the index patient had severe glomerulosclerosis and a kidney biopsy compatible with FD at the age of 30 years, along with cardiac involvement and a history of acroparesthesia since childhood, in keeping with a more classical Fabry phenotype., Conclusion: These findings highlight the large phenotypic heterogeneity associated with GLA mutations in FD and underline several important implications of MPS in the work-up of patients with unexplained kidney failure., Competing Interests: N.V.A.M.K. reports a grant from Health Holland. L.V. reports consulting fees (all to employer) from Sanofi Genzyme. M.H.d.B. reports honoraria (all to employer) from Amgen, AstraZeneca, Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzyme and Vifor Pharma, and grants from Sanofi Genzyme and Health Holland (grant numbers RVO/6320 and IMAGEN/LSHM20009). The other authors declare no competing interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Hypertension (HTN) is common following renal transplantation and it is associated with adverse effects on cardiovascular (CV) and graft health. Ambulatory blood pressure monitoring (ABPM) is the preferred method to characterize blood pressure (BP) status, since HTN misclassification by office BP (OBP) is quite common in this population. We performed a systematic review and meta-analysis aimed at determining the clinical utility of 24-h ABPM and its potential implications for the management of HTN in this population., Methods: Ovid-MEDLINE and PubMed databases were searched for interventional or observational studies enrolling adult kidney transplant recipients (KTRs) undergoing 24-h ABP readings compared with OBP or home BP. The main outcome was the proportion of KTRs diagnosed with HTN by ABPM, home or OBP recordings. Additionally, day-night BP variability and dipper/non-dipper status were assessed., Results: Forty-two eligible studies (4115 participants) were reviewed. A cumulative analysis including 27 studies (3481 participants) revealed a prevalence of uncontrolled HTN detected by ABPM of 56% [95% confidence interval (CI) 46-65%]. The pooled prevalence of uncontrolled HTN according to OBP was 47% (95% CI 36-58%) in 25 studies (3261 participants). Very few studies reported on home BP recordings. The average concordance rate between OBP and ABPM measurements in classifying patients as controlled or uncontrolled hypertensive was 66% (95% CI 59-73%). ABPM revealed HTN phenotypes among KTRs. Two pooled analyses of 11 and 10 studies, respectively, revealed an average prevalence of 26% (95% CI 19-33%) for masked HTN (MHT) and 10% (95% CI 6-17%) for white-coat HTN (WCH). The proportion of non-dippers was variable across the 28 studies that analysed dipping status, with an average prevalence of 54% (95% CI 45-63%)., Conclusions: In our systematic review, comparison of OBP versus ABP measurements disclosed a high proportion of MHT, uncontrolled HTN and, to a lesser extent, WCH in KTRs. These results suggest that HTN is not adequately diagnosed and controlled by OBP recordings in this population. Furthermore, the high prevalence of non-dippers confirmed that circadian rhythm is commonly disturbed in KTRs., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Angiotensin II type 1 receptor blockers (ARBs) lower blood pressure (BP) and proteinuria and reduce renal disease progression in many-but not all-patients. Reduction of dietary sodium intake improves these effects of ARBs. Dietary potassium intake affects BP and proteinuria. We set out to address the effect of potassium intake on BP and proteinuria response to losartan in non-diabetic proteinuric chronic kidney disease (CKD) patients., Methods: We performed a post hoc analysis of a placebo-controlled interventional cross-over study in 33 non-diabetic proteinuric patients (baseline mean arterial pressure and proteinuria: 105 mmHg and 3.8 g/day, respectively). Patients were treated for 6 weeks with placebo, losartan and losartan/hydrochlorothiazide (HCT), combined with a habitual (∼200 mmol/day) and low-sodium (LS) diet (<100 mmol/day), in randomized order. To analyse the effects of potassium intake, we categorized patients based on median split of 24-h urinary potassium excretion, reflecting potassium intake., Results: Mean potassium intake was stable during all six treatment periods. Losartan and losartan/HCT lowered BP and proteinuria in all treatment groups. Patients with high potassium intake showed no difference in the BP effects compared with patients with low potassium intake. The antiproteinuric response to losartan monotherapy and losartan combined with HCT during the habitual sodium diet was significantly diminished in patients with high potassium intake (20% versus 41%, P   =   0.011; and 48% versus 64%, P   =   0.036). These differences in antiproteinuric response abolished when shifting to the LS diet., Conclusions: In proteinuric CKD patients, the proteinuria, but not BP-lowering response to losartan during a habitual high-sodium diet was hampered during high potassium intake. Differences disappeared after sodium status change by LS diet., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Potassium often has a negative connotation in Nephrology as patients with chronic kidney disease (CKD) are prone to develop hyperkalaemia. Approaches to the management of chronic hyperkalaemia include a low potassium diet or potassium binders. Yet, emerging data indicate that dietary potassium may be beneficial for patients with CKD. Epidemiological studies have shown that a higher urinary potassium excretion (as proxy for higher dietary potassium intake) is associated with lower blood pressure (BP) and lower cardiovascular risk, as well as better kidney outcomes. Considering that the composition of our current diet is characterized by a high sodium and low potassium content, increasing dietary potassium may be equally important as reducing sodium. Recent studies have revealed that dietary potassium modulates the activity of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule (DCT). The DCT acts as a potassium sensor to control the delivery of sodium to the collecting duct, the potassium-secreting portion of the kidney. Physiologically, this allows immediate kaliuresis after a potassium load, and conservation of potassium during potassium deficiency. Clinically, it provides a novel explanation for the inverse relationship between dietary potassium and BP. Moreover, increasing dietary potassium intake can exert BP-independent effects on the kidney by relieving the deleterious effects of a low potassium diet (inflammation, oxidative stress and fibrosis). The aim of this comprehensive review is to link physiology with clinical medicine by proposing that the same mechanisms that allow us to excrete an acute potassium load also protect us from hypertension, cardiovascular disease and CKD., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Context: Although dietary potassium and sodium intake may influence calcium-phosphate metabolism and bone health, the effects on bone mineral parameters, including fibroblast growth factor 23 (FGF23), are unclear., Objective: Here, we investigated the effects of potassium or sodium supplementation on bone mineral parameters., Design, Setting, Participants: We performed a post hoc analysis of a dietary controlled randomized, blinded, placebo-controlled crossover trial. Prehypertensive individuals not using antihypertensive medication (n = 36) received capsules containing potassium chloride (3 g/d), sodium chloride (3 g/d), or placebo. Linear mixed-effect models were used to estimate treatment effects., Results: Potassium supplementation increased plasma phosphate (from 1.10 ± 0.19 to 1.15 ± 0.19 mmol/L, P = 0.004), in line with an increase in tubular maximum of phosphate reabsorption (from 0.93 ± 0.21 to 1.01 ± 0.20 mmol/L, P < 0.001). FGF23 decreased (114.3 [96.8-135.0] to 108.5 [93.5-125.9] RU/mL, P = 0.01), without change in parathyroid hormone and 25-hydroxy vitamin D3. Fractional calcium excretion decreased (from 1.25 ± 0.50 to 1.11 ± 0.46 %, P = 0.03) without change in plasma calcium. Sodium supplementation decreased both plasma phosphate (from 1.10 ± 0.19 to 1.06 ± 0.21 mmol/L, P = 0.03) and FGF23 (from 114.3 [96.8-135.0] to 108.7 [92.3-128.1] RU/mL, P = 0.02). Urinary and fractional calcium excretion increased (from 4.28 ± 1.91 to 5.45 ± 2.51 mmol/24 hours, P < 0.001, and from 1.25 ± 0.50 to 1.44 ± 0.54 %, P = 0.004, respectively)., Conclusions: Potassium supplementation led to a decrease in FGF23, which was accompanied by increase in plasma phosphate and decreased calcium excretion. Sodium supplementation reduced FGF23, but this was accompanied by decrease in phosphate and increase in fractional calcium excretion. Our results indicate distinct effects of potassium and sodium intake on bone mineral parameters, including FGF23., Clinical Trial Registration Number: NCT01575041., (© Endocrine Society 2020.)

Background Isolated systolic hypertension (ISH) of the young has been associated with both normal and increased cardiovascular risk, which has been attributed to differences in central systolic blood pressure and arterial stiffness. Methods We assessed the prevalence of ISH of the young and compared differences in central systolic blood pressure and arterial stiffness between ISH and other hypertensive phenotypes in a multi-ethnic population of 3744 subjects (44% men), aged <40 years, participating in the HELIUS study. Results The overall prevalence of ISH was 2.7% (5.2% in men and 1.0% in women) with the highest prevalence in individuals of African descent. Subjects with ISH had lower central systolic blood pressure and pulse wave velocity compared with those with isolated diastolic or systolic-diastolic hypertension, resembling central systolic blood pressure and pulse wave velocity values observed in subjects with high-normal blood pressure. In addition, they had a lower augmentation index and larger stroke volume compared with all other hypertensive phenotypes. In subjects with ISH, increased systolic blood pressure amplification was associated with male gender, Dutch origin, lower age, taller stature, lower augmentation index and larger stroke volume. Conclusion ISH of the young is a heterogeneous condition with average central systolic blood pressure values comparable to individuals with high-normal blood pressure. On an individual level ISH was associated with both normal and raised central systolic blood pressure. In subjects with ISH of the young, measurement of central systolic blood pressure may aid in discriminating high from low cardiovascular risk.

Background: Patients with end-stage renal disease (ESRD) have a decreased quality of life (QoL), which is attributable in part to ESRD-related hyperparathyroidism (HPT). Both cinacalcet and parathyroidectomy (PTx) are treatments for advanced HPT, but their effects on QoL are unclear. We performed a systematic review to evaluate the impact of cinacalcet and PTx on QoL., Methods: A systematic literature search was performed using PubMed and EMBASE databases to identify relevant articles. The search was based on the following keywords: 'parathyroidectomy' or 'cinacalcet', 'secondary hyperparathyroidism' or 'renal hyperparathyroidism' combined with 'quality of life' or 'SF-36' or 'symptomatology'. Only studies reporting on QoL at baseline and during follow-up were included. QoL scores were extracted from the selected manuscripts and weighted means were calculated. Due to a lack of available data on QoL improvement in patients using cinacalcet, a meta-analysis could not be performed., Results: In all, eight articles reached our inclusion criteria. Of this, five articles reported the effect of PTx on QoL. All PTx studies were observational and non-controlled. The physical component scores of the 36-item Medical Outcomes Study Short-Form Health Survey increased significantly with a weighted mean of 35.5% (P < 0.05). Mental component scores increased with 13.7% (P < 0.05). Parathyroidectomy assessment of symptom scores improved from 561 preoperatively to 302 postoperatively (-259 points; -46.2%). Visual analogue scale scores decreased significantly for skin itching (46.6%), joint pain (30.4%) and muscle weakness (28.7%) (P < 0.05). Three studies on the effect of cinacalcet on QoL were included, including one randomized controlled trial. None of these studies showed significant improvement of physical component and mental component scores., Conclusions: PTx improved QoL in patients treated for ESRD-related HPT, whereas cinacalcet did not. The difference in impact between PTx and cinacalcet on QoL has not been compared directly., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Human immunodeficiency virus (HIV)-infected individuals are at increased risk of chronic kidney disease (CKD). Human immunodeficiency virus infection, traditional CKD risk factors, and combination antiretroviral therapy (cART) may all contribute., Methods: We compared prevalence of renal impairment (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2), albuminuria (albumin/creatinine ratio ≥3 mg/mmol), and proximal renal tubular dysfunction (retinol-binding protein/creatinine ratio >2.93μg/mmol and/or fractional phosphate excretion >20% with plasma phosphate <0.8 mmol/L) in 596 HIV-infected and 544 HIV-uninfected AGEhIV Cohort Study participants. We also assessed whether being HIV-infected on cART, with follow-up censored when cART regimen was modified, was associated with greater eGFR decline or worsening albuminuria (increase ≥10%/year with change in albuminuria category)., Results: Human immunodeficiency virus infection was independently associated with renal impairment (adjusted odds ratio [aOR] = 2.1; 95% confidence interval [CI] = 1.0-4.4), albuminuria (aOR = 5.8; 95% CI = 3.7-9.0), and proximal renal tubular dysfunction (aOR = 7.0; 95% CI = 4.9-10.2]). Among 377 HIV-infected and 479 HIV-uninfected individuals (median follow-up = 3.9/4.1 years, respectively) included in longitudinal analyses, being HIV-infected and remaining on unmodified cART was independently associated with greater eGFR decline (-0.56; 95% CI = -0.87 to -0.24 mL/min/1.73m2/year) and worsening albuminuria (aOR = 2.3; 95% CI = 1.3-4.0)., Conclusions: In these middle-aged individuals, HIV infection was independently associated with renal impairment, albuminuria, and proximal renal tubular dysfunction. Human immunodeficiency virus-infected individuals on cART (predominantly containing tenofovir disoproxil fumarate) were also more likely to experience eGFR decline and worsening albuminuria compared with HIV-uninfected individuals., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Chronic kidney disease (CKD) is an important comorbidity during human immunodeficiency virus (HIV) infection. Historically, HIV-associated nephropathy has been the predominant cause of CKD and has primarily been observed in people of African ancestry. This study aims to investigate the role of ethnicity in relation to CKD risk in recent years., Methods: Analyses were performed including 16 836 patients from the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. Baseline was defined as the first available creatinine level measurement after 1 January 2007; CKD was defined as a glomerular filtration rate of <60 mL/min/1.73 m(2). The associations between ethnicity and both prevalent CKD at baseline and incident CKD during follow-up were analyzed., Results: The prevalence of baseline CKD was 2.7% (460 of 16 836 patients). Birth in a sub-Saharan African country (hereafter, "SSA origin") was significantly associated with baseline CKD (adjusted odds ratio 1.49; 95% confidence interval [CI], 1.04-2.13). During follow-up (median duration, 4.7 years; interquartile range, 2.4-5.2), the rate of incident CKD was 6.0 events per 1000 person-years. The risk of newly developing CKD was similar between patients of SSA origin and those born in Western Europe, Australia, or New Zealand (adjusted hazard ratio, 1.00; 95% CI, .63-1.59)., Conclusions: Among HIV-infected patients in the Netherlands, being of SSA origin was associated with a higher baseline CKD prevalence but had no impact on newly developing CKD over time. This suggests a shift in the etiology of CKD from HIV-associated nephropathy toward other etiologies., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Renin-angiotensin aldosterone system (RAAS) blockade only partly reduces blood pressure, proteinuria and renal and cardiovascular risk in chronic kidney disease (CKD) but often requires sodium targeting [i.e. low sodium diet (LS) and/or diuretics] for optimal efficacy. However, both under- and overtitration of sodium targeting can easily occur. We evaluated whether N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of volume expansion, predicts the benefits of sodium targeting in CKD patients., Methods: In a cross-over randomized controlled trial, 33 non-diabetic CKD patients (proteinuria 3.8 ± 0.4 g/24 h, blood pressure 143/86 ± 3/2 mmHg, creatinine clearance 89 ± 5 mL/min) were treated during 6-week periods with placebo, angiotensin receptor blockade (ARB; losartan 100 mg/day) and ARB plus diuretics (losartan 100 mg/day plus hydrochlorothiazide 25 mg/day), combined with LS (93 ± 52 mmol Na(+)/24 h) and regular sodium diet (RS; 193 ± 62 mmol Na(+)/24 h, P < 0.001 versus LS), in random order. As controls, 27 healthy volunteers were studied., Results: NT-proBNP was elevated in patients during placebo + RS [90 (60-137) versus 35 (27-45) pg/mL in healthy controls, P = 0.001]. NT-proBNP was lowered by LS, ARB and diuretics and was normalized by ARB + diuretic + LS [39 (26-59) pg/mL, P = 0.65 versus controls]. NT-proBNP levels above the upper limit of normal (>125 pg/mL) predicted a larger reduction of blood pressure and proteinuria by LS and diuretics but not by ARB, during all steps of the titration regimen., Conclusions: Elevated NT-proBNP levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of sodium targeting, but not RAAS blockade, in proteinuric CKD patients. Importantly, this applies to the untreated condition, as well as to the subsequent treatment steps, consisting of RAAS blockade and even RAAS blockade combined with diuretics. NT-proBNP can be a useful tool to identify CKD patients in whom sodium targeting can improve blood pressure and proteinuria.

Background: Renin-angiotensin-aldosterone system (RAAS) blockade improves prognosis in renal patients, but usually requires diuretic co-treatment. RAAS blockade can decrease erythropoietin (EPO) and/or haemoglobin (Hb) levels. Diuretics decrease EPO in rodents, but their effect on EPO and Hb in humans is unknown., Methods: Proteinuric renal patients with preserved renal function were treated during 6-week periods with placebo, losartan 100 mg/day (LOS) and LOS plus hydrochlorothiazide 25 mg/day (LOS/HCT), in random order., Results: Hb was inversely related to proteinuria, and EPO levels were inappropriately low in relation to Hb. Hb was lowered by LOS with and without HCT. EPO was decreased by LOS/HCT, but not by LOS., Conclusions: EPO and Hb are reduced by HCT added to LOS in proteinuric renal patients with preserved renal function. We hypothesize that EPO reduction by HCT is caused by a decrease in renal oxygen requirement, which is the main stimulus for EPO production, due to the inhibition of active tubular sodium reabsorption. Further studies should explore the exact mechanism of this phenomenon and its clinical impact.

Background: Renoprotection is predicted by the antiproteinuric efficacy of a pharmacological agent. Non-steroidal anti-inflammatory drugs (NSAIDs) interfering non-selectively in the prostaglandin system have strong antiproteinuric potency without reduction of systemic blood pressure. The effect of the selective COX-2 inhibitor rofecoxib in proteinuric patients is unknown, granted recently reported detrimental effects in non-renal patients. Short-term effects of rofecoxib on proteinuria and blood pressure as compared to NSAID and RAAS blockade were studied., Methods: Sixteen stable patients [mean proteinuria 4.4 g/ day; MAP 103 mmHg)] were included after a wash-out period. Hydrochlorothiazide 12.5 mg QD was given throughout. Additional blood pressure control was ensured by non-RAAS blocking antihypertensive agents. Patients received rofecoxib 25 mg QD, 50 mg QD and indomethacin 75 mg BID in randomized order for 4 weeks. Thereafter, a subset of the included patients (n = 11) received lisinopril 40 mg QD for 6 weeks preceded by a wash-out period., Results: Rofecoxib exerted a dose-dependent antiproteinuric effect. As compared to rofecoxib 25 and 50 mg, indomethacin was more effective [-18, -28 versus -49% (n = 16; P < 0.05)]. As compared to rofecoxib 50 mg, lisinopril was more effective [-21 versus -51% (n = 11; P < 0.05)]. No significant blood pressure changes were observed after rofecoxib and indomethacin, whereas lisinopril had a significant antihypertensive effect., Conclusion: Selective COX-2 inhibition reduces proteinuria without reduction of systemic blood pressure, pointing towards a specific renal effect, and may serve as a novel non-hypotensive adjunct antiproteinuric treatment.

Background: Lipid derangements are assumed to contribute to the elevated cardiovascular risk in proteinuric patients. The impact of proteinuria on reverse cholesterol transport (RCT) is unknown. The first step in RCT, cellular cholesterol efflux to plasma, may be altered in proteinuria, consequent to changes in pre-beta high-density lipoprotein (HDL) formation and plasma phospholipid transfer protein (PLTP) activity., Methods: In six non-diabetic male patients with nephrotic-range proteinuria and 12 matched healthy men, plasma (apo)lipoproteins, pre-beta HDL formation, PLTP activity as well as the ability of plasma to promote cholesterol efflux out of cultured human skin fibroblasts were determined. These variables were also measured in response to antiproteinuric treatment, consisting of single and dual RAAS blockade by losartan and lisinopril., Results: Plasma total cholesterol (P<0.05), triglycerides (P<0.05), apolipoprotein (apo) A-I (P<0.001), apo B (P<0.001), PLTP activity (P<0.005) and pre-beta HDL formation (P<0.001) were higher in proteinuric patients. Cellular cholesterol efflux to plasma from proteinuric patients was 41% higher than to plasma from healthy subjects (P<0.001). Reduction of proteinuria from 5.0 to 1.4 g/day by dual RAAS blockade was associated with a 23% reduction in plasma apo B levels (P<0.05). Pre-beta HDL formation and plasma PLTP activity did not change significantly. Combined antiproteinuric treatment did not reduce the elevated cellular cholesterol efflux., Conclusion: Cellular cholesterol efflux to plasma from patients with nephrotic-range proteinuria is enhanced, in conjunction with elevated pre-beta HDL formation and plasma PLTP activity. These changes may attenuate the cardiovascular risk associated with proteinuria-associated hyperlipidaemia. Antiproteinuric therapy lowers plasma apo B, but does not affect cell-derived cholesterol efflux, suggesting that this therapy beneficially affects cardiovascular risk in proteinuric patients.