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Background: Among persons with type 1 diabetes mellitus (T1DM) low concentrations of magnesium have been reported. Previous (small) studies also suggested a relation of hypomagnesemia with (poor) glycaemic control and complications. We aimed to investigate the magnitude of hypomagnesemia and the associations between magnesium with parameters of routine T1DM care in a population of unselected outpatients. Methods: As part of a prospective cohort study, initially designed to measure quality of life and oxidative stress, data from 207 patients with a mean age of 45 [standard deviation (SD) 12] years, 58% male, diabetes duration 22 [interquartile range (IQR) 16, 31] years and glycated haemoglobin (HbA1c) of 60 (SD 11) mmol/mol [7.6 (SD 1.0)%] were examined. Hypomagnesemia was defined as a concentration below

BACKGROUND: Cardiovascular disease is one of the major causes of death worldwide. Assessing the risk for cardiovascular disease is an important aspect in clinical decision making and setting a therapeutic strategy, and the use of serological biomarkers may improve this. Despite an overwhelming number of studies and meta-analyses on biomarkers and cardiovascular disease, there are no comprehensive studies comparing the relevance of each biomarker. We performed a systematic review of meta-analyses on levels of serological biomarkers for atherothrombosis to compare the relevance of the most commonly studied biomarkers. METHODS AND FINDINGS: Medline and Embase were screened on search terms that were related to "arterial ischemic events" and "meta-analyses". The meta-analyses were sorted by patient groups without pre-existing cardiovascular disease, with cardiovascular disease and heterogeneous groups concerning general populations, groups with and without cardiovascular disease, or miscellaneous. These were subsequently sorted by end-point for cardiovascular disease or stroke and summarized in tables. We have identified 85 relevant full text articles, with 214 meta-analyses. Markers for primary cardiovascular events include, from high to low result: C-reactive protein, fibrinogen, cholesterol, apolipoprotein B, the apolipoprotein A/apolipoprotein B ratio, high density lipoprotein, and vitamin D. Markers for secondary cardiovascular events include, from high to low result: cardiac troponins I and T, C-reactive protein, serum creatinine, and cystatin C. For primary stroke, fibrinogen and serum uric acid are strong risk markers. Limitations reside in that there is no acknowledged search strategy for prognostic studies or meta-analyses. CONCLUSIONS: For primary cardiovascular events, markers with strong predictive potential are mainly associated with lipids. For secondary cardiovascular events, markers are more associated with ischemia. Fibrinogen is a strong predictor for primary stroke.

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.)

Semaglutide reduces albuminuria and the risk of kidney disease progression in patients with type 2 diabetes and chronic kidney disease (CKD). We conducted a randomized placebo-controlled double-blind clinical trial in adults with CKD (estimated glomerular filtration rate (eGFR) ≥25 ml min -1  1.73 m - 2 and urine albumin-to-creatinine ratio (UACR) ≥30 and <3,500 mg g -1 ) and body mass index ≥27 kg m - 2 . Participants were randomized to semaglutide 2.4 mg per week or placebo. The primary endpoint was percentage change from baseline in UACR at week 24. Safety was monitored throughout. Overall, 125 participants were screened, of whom 101 were randomized to semaglutide (n = 51) or placebo (n = 50). Mean age was 55.8 (s.d. 12) years; 40 participants (39.6%) were female; median UACR was 251 mg g -1 (interquartile range 100, 584); mean eGFR was 65.0 (s.d. 25) ml min -1  1.73 m - 2 ; and mean body mass index was 36.2 (s.d. 5.6) kg m - 2 . Chronic glomerulonephritis (n = 25) and hypertensive CKD (n = 27) were the most common CKD etiologies. Treatment for 24 weeks with semaglutide compared to placebo reduced UACR by -52.1% (95% confidence interval -65.5, -33.4; P < 0.0001). Gastrointestinal adverse events were more often reported with semaglutide (n = 30) than with placebo (n = 15). Semaglutide treatment for 24 weeks resulted in a clinically meaningful reduction in albuminuria in patients with overweight/obesity and non-diabetic CKD. ClinicalTrials.gov registration: NCT04889183 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Fatigue is an important symptom for many patients, including patients with kidney disease. Cognitive biases, such as attentional bias and self-identity bias, are thought to influence fatigue. Cognitive bias modification (CBM) training is a promising technique to counter fatigue., Objective: We aimed to evaluate a CBM training among patients with kidney disease and health care professionals (HCPs) and assess acceptability and applicability in the clinical setting using an iterative design process to evaluate expectations and experiences with the training., Methods: This was a longitudinal, qualitative, and multiple stakeholder-perspective usability study in which we interviewed end users and HCPs during the prototyping phase and after the end of training. We conducted semistructured interviews with 29 patients and 16 HCPs. The interviews were transcribed and analyzed thematically. Next to a general evaluation of the training, the acceptability of the training was evaluated using the Theoretical Framework of Acceptability, and applicability was assessed by evaluating obstacles and solutions for implementation in the kidney care setting., Results: Generally, participants were positive about the training and its applicability. The biggest negatives were doubts about effectiveness and annoyance about the repetitive character of CBM. Acceptability was judged with a mixed evaluation, with a negative evaluation of perceived effectiveness; mixed results for burden, intervention coherence, and self-efficacy; and positive results for affective attitude, ethicality, and opportunity costs. Barriers for applicability were patients' varying computer skills, subjectivity of fatigue, and integration with regular treatment (eg, the role of HCPs). Possible solutions included assigning representatives among nurses, offering training on an app, and providing assistance via a help desk. The iterative design process, including repeated waves of testing user expectations and experiences, yielded complementary data., Conclusions: To the best of our knowledge, this study is the first to introduce a CBM training targeting fatigue. Furthermore, this study provides one of the first user evaluations of a CBM training, both among patients with kidney disease and their care providers. Overall, the training was evaluated positively, although acceptability showed mixed results. Applicability was positive although barriers were identified. The proposed solutions require further testing, preferably following the same frameworks, as the iteration in this study contributed positively to the quality of the training. Therefore, future research should follow the same frameworks and consider stakeholders and end users in eHealth intervention design., (©Jody Geerts, Marcel Pieterse, Goos Laverman, Femke Waanders, Nicole Oosterom, Jacqueline Slegten, Elske Salemink, Christina Bode. Originally published in JMIR Formative Research (https://formative.jmir.org), 29.05.2023.)

Introduction: Kidney failure negatively affects opportunities for work participation. Little is known about work functioning of employed CKD patients. This study investigates work-related outcomes, and examines associations between patient characteristics and employment status., Methods: We performed a cross-sectional survey study in nine nephrology outpatient clinics in the Netherlands among working age (18-67 years) CKD Stage G3b-G5, dialysis and transplant patients (n = 634; mean age 53.4 years (SD 10); 53% male; 47% Stage G3b-G5, 9% dialysis, 44% transplantation). We assessed employment status, work disability, work-related characteristics (i.e., work situation, working hours, job demands), work functioning (i.e., perceived ability to work, productivity loss, limitations in work), work environment (i.e., work accommodations, psychosocial work environment), as well as health status and fatigue., Results: Sixty-five percent were employed reporting moderate work ability. Of those, 21% received supplementary work disability benefits, 37% were severely fatigued, 7% expected to drop out of the workforce, and 49% experienced CKD-related work limitations. Work accommodations included reduced working hours, working at a slower pace, adjustment of work tasks or work schedule, and working from home. Multivariable analysis of sustained employment showed associations with younger age, male gender, higher level of education, better general and physical health and pre-emptive transplantation. Transplant patients had the highest work ability and highest expectation to maintain work. Dialysis patients had the highest productivity loss and perceived the most limitations regarding functioning in work. Stage G3b-G5 patients reported the lowest social support from colleagues and highest conflict in work and private life., Conclusions: Employed CKD patients experience difficulties regarding functioning in work requiring adjustment of work or partial work disability. In addition to dialysis patients, stage G3b-G5 patients are vulnerable concerning sustained employment and work functioning., (© 2022. The Author(s).)

Polycyclic aromatic hydrocarbons (PAHs) have been a problem in the environment for an extended period. They are mostly derived from petroleum, coal tar and oil spills that travel and are immobilized in wastewater/water sources. Their presence in the environment causes a hazard to humans due to their toxicity and carcinogenic properties. In the study, coal tar was analyzed using Gas Chromatography-Mass Spectrometry (GC-MS) and a concentration of 787.97 mg/L of naphthalene, followed by 632.15 mg/L of phenanthrene were found to be in the highest concentrations in the various water sources such as sewage, alkaline and acid mine drainage. A design column was used to investigate the leaching process and assessments were conducted on 300 mL of the various water sources mentioned, with 5 g of coal tar added and with monitoring for 4 weeks. The influence of the physiochemical properties of the receiving water sources, such as sewage, and acid and alkaline mine drainage, on the release of PAHs from the coal tar was assessed. The acidic media was proven to have the highest release of PAHs, with a total concentration of 7.1 mg/L of released PAHs, followed by 1.2 mg/L for the sewage, and lastly, 0.32 mg/L for the alkaline mine drainage at room temperature.

This study investigated the effect of carbon sources ( n  = 2) on the performance of a microbial community in an anaerobic moving-bed biofilm reactor (MBBR) treating acid mine drainage (AMD). The 1.5 L anaerobic MBBR was operated across a range of hydraulic retention times - HRT's (3-18 days), using different substrates, i.e. brewing wastewater and lactate as sole carbon sources and electron donors. Maximum sulphate reduction and chemical oxygen demand (COD) consumption rate was 21.94 and 24.28 mg SO 4 2 - L -1 h -1 , and 0.473 and 0.697 mg COD L -1 d -1 for brewing wastewater and lactate supplemented bioreactors, respectively, at an HRT of 3 days. The maximum COD/ SO 4 2 - ratio was found to be 2.564 in the bioreactor supplemented with brewing wastewater at an HRT of 15 days. The metal removal above 70% in the system supplemented with brewing wastewater followed the order; Be 2+  > Fe 2+  > Sr 2+  > Pb 2+  > Mg 2+  > Cu 2+  > Zn 2+  > Li 1+  > Ca 2+ in comparison to the system supplemented with lactate, Be 2+  > Fe 2+  > Sr 2+  > Mg 2+  > Cu 2+  > Li 1+  > Zn 2+  > Pb 2+ after an HRT of 18 days. Complete removal of beryllium (II) was observed irrespective of the carbon source used. The results clearly showed that brewing wastewater can be deployed as a nutritional supplement in environmental remediation of AMD.

[Figure: see text].

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.)

Introduction: Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus (T1DM) characterized by hyperglycemia and metabolic acidosis. Hypophosphatemia in DKA often occurs during hospital admittance for DKA. Literature on the magnitude, determinants and consequences of hypophosphatemia in DKA is scarce. Primary aim of this study was to investigate the incidence and consequences of hypophosphatemia during hospitalisation for DKA., Research Design and Methods: Cohort study among individuals with T1DM who were admitted for DKA between 2005 and 2020 in an academic and a non-academic hospital. Multivariate regression models were performed to investigate determinants of the lowest phosphate during the treatment of DKA., Results: A total of 127 episodes of DKA among 80 individuals were identified. Age at DKA presentation was 28 (22-46) years, 45% of the cases was female, diabetes duration was 13.2 (8.9-25.5) years with glycosylated hemoglobin levels of 91.9±26.2 mmol/mol. In 9% of all cases, DKA was the first presentation of T1DM. Lowest phosphate levelss reported during the treatment phase were 0.54 (0.32-0.83) mmol/L and hypophosphatemia was present in 74% (62/84). The time to lowest phosphate was 16 (8-23) hours. In multivariate analysis, baseline bicarbonate and hemoglobin at admission were significantly associated with the lowest phosphate level reported. No adverse effects of hypophosphatemia on hospital stay duration, morbidity or mortality were found, even if left untreated., Conclusions: Hypophosphatemia during DKA is common and increases with severe acidosis. However, in this study it was not related to adverse outcomes. Although limitations of this retrospective study should be taken into account, the routine and repeated measurement of phosphate levels in DKA could be reconsidered, provided that possible symptoms related to hypophosphatemia are monitored., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Serum calcification propensity is emerging as an independent predictor for cardiovascular outcomes in high-risk populations. Calcification propensity can be monitored by the maturation time of calciprotein particles in serum (T 50 test). A low T 50 value is an independent determinant of cardiovascular morbidity and mortality in various populations. Aim was to investigate the T 50 and its relationship to type 2 diabetes mellitus., Research Design and Methods: Using nephelometry, serum T 50 was cross-sectionally measured in 932 stable patients with type 2 diabetes mellitus (55% male) with a median age of 66 (62-75) years, diabetes duration of 6.5 (3.0-10.2) years and hemoglobin A1c (HbA1c) of 49 (44-54) mmol/mol., Results: Serum T 50 was normally distributed with a mean value of 261±66 min. In linear regression, serum T 50 was lower in women and current smokers. A lower T 50 value was found in patients with a higher HbA1c or higher systolic blood pressure, insulin users and patients with a longer history of diabetes. The association with HbA1c was independent of other determinants in multivariable analysis. There was no association between T 50 and previous macrovascular events or the presence of microvascular disease., Conclusions: Serum calcification propensity is independently associated with glycemic control, suggesting that a lower HbA1c may be associated with better cardiovascular outcomes. Retrospective analysis could not establish an association between a history of macrovascular events and T 50 , and prospective studies will have to be performed to address this hypothesis., Trial Registration Number: NCT01570140., Competing Interests: Competing interests: All authors have approved the final version of the manuscript. AP is an employee and stockholder of Calciscon., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Among persons with type 1 diabetes mellitus (T1DM) low concentrations of magnesium have been reported. Previous (small) studies also suggested a relation of hypomagnesemia with (poor) glycaemic control and complications. We aimed to investigate the magnitude of hypomagnesemia and the associations between magnesium with parameters of routine T1DM care in a population of unselected outpatients., Methods: As part of a prospective cohort study, initially designed to measure quality of life and oxidative stress, data from 207 patients with a mean age of 45 [standard deviation (SD) 12] years, 58% male, diabetes duration 22 [interquartile range (IQR) 16, 31] years and glycated haemoglobin (HbA1c) of 60 (SD 11) mmol/mol [7.6 (SD 1.0)%] were examined. Hypomagnesemia was defined as a concentration below <0.7 mmol/l., Results: Mean magnesium concentration was 0.78 (SD 0.05) mmol/l. A deficiency was present in 4.3% of participants. Among these persons, mean concentration was 0.66 (SD 0.03) mmol/l. There was no correlation between magnesium and HbA1c at baseline ( r  = -0.014, p  = 0.843). In multivariable analysis, free thiols (reflecting the degree of oxidative stress) were significantly and negatively associated with magnesium concentrations., Conclusion: In this cohort of T1DM outpatients, the presence of hypomagnesemia was infrequent and, if present, relative mild. Magnesium was not associated with glycaemic control nor with presence of micro- and macrovascular complications. Although these results need confirmation, in particular the negative association of magnesium with free thiols, this suggests that hypomagnesemia is not a relevant topic in routine care for people with T1DM., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: Serum calcification propensity can be monitored using the maturation time of calciprotein particles in serum (T 50 test). A shorter T 50 indicates greater propensity to calcify; this is an independent determinant of cardiovascular disease. As the intraperitoneal (IP) route of insulin administration mimics the physiology more than the subcutaneous (SC) route in persons with type 1 diabetes (T1DM), we hypothesized that IP insulin influences determinants of calcium propensity and therefore result in a longer T 50 than SC insulin administration., Methods: Prospective, observational case-control study. Measurements were performed at baseline and at 26 weeks in age and gender matched persons with T1DM., Results: A total of 181 persons, 39 (21.5%) of which used IP and 142 (78.5%) SC insulin were analysed. Baseline T 50 was 356 (45) minutes. The geometric mean T 50 significantly differed between both treatment groups: 367 [95% confidence interval (CI) 357, 376] for the IP group and 352 (95% CI 347, 357) for the SC group with a difference of -15 (95% CI -25, -4) minutes, in favour of IP treatment. In multivariable analyses, the IP route of insulin administration had a positive relation on T 50 concentrations while higher age, triglycerides and phosphate concentrations had an inverse relation., Conclusion: Among persons with T1DM, IP insulin administration results in a more favourable calcification propensity time then SC insulin. It has yet to be shown if this observation translates into improved cardiovascular outcomes., Competing Interests: Conflict of interest statement: AP is an employee and stockholder of Calciscon. All other authors declare they have no conflict of interest., (© The Author(s), 2020.)

Introduction: Type 1 diabetes mellitus (T1DM) is associated with inflammation and the production of reactive oxygen species (ROS). Systemically, free thiols (R-SH) can be oxidized by ROS and circulating R-SH concentrations may directly reflect the systemic redox status. In this study the association between R-SH and clinical parameters of T1DM, including glycated haemoglobin A1c (HbA1c), was investigated. This is of particular interest since thiols are amendable to therapeutic intervention., Methods: As part of a prospective cohort study, data from 216 patients with a mean age of 45 (12) years, 57% male, diabetes duration 22 (16, 30) years and HbA1c of 60 (11) mmol/mol were examined. Baseline data were collected in 2002 and follow-up data in 2018. Cox proportional hazards regression analysis, with age, sex, HbA1c and R-SH, was used to assess prognostic factors for the development of complications., Results: At baseline, the plasma concentration of R-SH was 281.8 ± 34.0 μM. In addition to a lower concentration of NT-proBNP in the highest R-SH quartile (305-379 µM) there were no differences in baseline characteristics between the quartiles of R-SH. The Pearson correlation coefficient for R-SH and NT-proBNP was -0.290 ( p  < 0.001). No significant correlation between R-SH and baseline HbA1c ( r  = -0.024, p  = 0.726) was present. During follow-up, 42 macrovascular and 92 microvascular complications occurred. In Cox regression, R-SH was not a prognostic factor for the development of microvascular [hazard ratio (HR) 0.999 (95% confidence interval (CI) 0.993, 1.005)] and macrovascular [HR 0.993 (95% CI 0.984, 1.002)] complications., Conclusions: In addition to a negative association with NT-proBNP, no relevant relationships between R-SH and parameters of T1DM, including HbA1c, were present in this study., Competing Interests: Conflict of interest statement: The authors declare that they have no conflict of interest., (© The Author(s), 2020.)

Aims: Among persons with type 2 diabetes mellitus (T2DM) hypomagnesaemia has been reported in 14-48% of patients. This may be of significance given the emerging associations of hypomagnesaemia with glucometabolic disturbances and possibly even complications. We assessed the prevalence of hypomagnesaemia and its determinants, in a well-defined cohort of persons with T2DM treated in primary care., Methods: Observational cohort study among persons with T2DM treated in primary care in the Northeast of the Netherlands. Magnesium was measured using a colorimetric endpoint assay (Roche). Hypomagnesaemia was defined as a serum magnesium level <0.70 mmol/L. Pearson correlations were performed to correlate variables with serum magnesium. Next, a stepwise backward regression model was made., Results: Data of 929 persons (55% male) with a mean age of 65 (± 10) years, diabetes duration 6.5 [3.0-10.1] years, and HbA1c concentration 6.7 (± 0.7)% (50 (± 9) mmol/mol) were analysed. Serum magnesium was 0.79 (± 0.08) mmol/L. The percentage of persons with magnesium deficiency was 9.6%. Age, diabetes duration, BMI, HbA1c, use of metformin, sulfonylurea derivatives, and DPP4 inhibitors were negatively associated with magnesium concentrations. In contrast, LDL cholesterol and serum creatinine were positively associated serum magnesium., Conclusions: Hypomagnesaemia was present in 9.6% of T2DM patients treated in primary care. This percentage is remarkably lower than reported previously, possibly due to the unselected nature of our population. Concerning T2DM-related factors, only BMI, HbA1c and the use of metformin, sulfonylurea derivatives and DPP4 inhibitors correlated negatively with magnesium concentrations.

Aims: Increased vascular calcification could be an underlying mechanism of cardiovascular complications in type 1 diabetes mellitus (T1DM). Calcificationpropensitycan be monitored by the maturation time of calciprotein particles in serum (T 50 test). A high calcification propensity (i.e. low T 50 -value) is an independent determinant of mortality in various populations. Aim was to investigate T 50 levels with indices of calcium metabolism and disease status in T1DM patients., Methods: As part of a prospective cohort study, T1DM patients were examined annually. At baseline T 50 was determined in 216 (77%) patients (57% male) with a mean age of 45 (12) years, diabetes duration 22 [15.8, 30.4] years and HbA1c of 60 (12) mmol/mol (7.6 (1.0) %). Baseline data were collected in 2002 and follow-up data were collected in 2018., Results: The T 50 time was normally distributed with a mean of 339 (60) minutes. Patients in the highest tertile of T 50 (range 369-466) were older, had lower phosphate and PTH and higher magnesium and vitamin D concentrations as compared to the middle (range 317-368) and lowest (range 129-316) tertiles, while eGFR was comparable between groups. During follow-up of 15 years, 43 patients developed a macrovascular complication and 26 patients died. In regression analysis, T 50 was not a prognostic factor for the development of complications or mortality., Conclusions: The T 50 time was associated with indices of increased mineral stress, but not with the development of long-term macrovascular complications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Surgery for infective endocarditis imposes great challenges in post-operative circulatory and pulmonary support but the role of veno-arterial extra-corporal membrane oxygenation in this respect is unclear., Methods: All patients undergoing veno-arterial extra-corporal membrane oxygenation after infective endocarditis surgery were analysed for age, gender, medical history, microorganisms, clinical outcome, complications and surgical procedure., Results: Between 2012 and 2016, 13 patients received veno-arterial extra-corporal membrane oxygenation following infective endocarditis surgery. The median age was 62 years (33-73) and 8/13 were male. Previous cardiac surgery was present in nine patients. Surgery for infective endocarditis consisted of a Bentall procedure in 10 patients, 2 of which received concomitant mitral valve surgery and 2 received concomitant coronary artery bypass graft. Valvular surgery alone was performed in three patients. Mortality on veno-arterial extra-corporal membrane oxygenation was 62% (8/13). Mortality during intensive care unit stay was 77% (10/13). Survival to discharge was 23% (3/13). One patient reached the 1 year survival point. Two patients who survived to discharge have not yet reached the 1 year survival point. Patient-related complications occurred in 54% (7/13) of patients and consisted of haemorrhage at the cannula site in four patients, leg ischaemia in one patient, haemorrhage at another site in one patient and infection of the cannula in one patient. Extra-corporal membrane oxygenation hardware-related complications occurred in one case consisting of clot formation in the oxygenator., Conclusion: Veno-arterial extra-corporal membrane oxygenation in post-cardiotomy patients who were operated on for infective endocarditis is feasible, but outcome is poor.

Aims: Intraperitoneal (IP) insulin administration is a last-resort treatment option for selected patients with type 1 diabetes mellitus (T1DM). As the IP route of insulin administration mimics the physiology more closely than the subcutaneous (SC) route, we hypothesized that IP insulin would result in less oxidative stress (expressed as systemic level of free sulphydryl (R-SH) content) compared to SC insulin in subjects with T1DM., Materials and Methods: Prospective, observational case-control study. Serum thiol measurements were performed at baseline and at 26 weeks in age- and gender-matched patients with T1DM. Serum-free thiols, compounds with a R-SH group that are readily oxidized by reactive oxygen species, are considered to be a marker of systemic redox status., Results: A total of 176 patients, 39 of which used IP and 141 SC insulin therapy were analysed. Mean baseline R-SH concentration was 248 (31) μmol/L. In multivariable analysis, the route of insulin therapy had no impact on baseline R-SH levels. The estimated geometric mean concentrations of R-SH did not differ significantly between both groups: 264 (95% CI 257, 270) for the IP group and 258 (95% CI 254, 261) for the SC group with a difference of 6 (95% CI -2, 14) μmol/L., Conclusions: Based on R-SH as a marker of systemic oxidative stress, these findings demonstrate that the route of insulin administration, IP or SC, does not influence systemic redox status in patients with T1DM., Competing Interests: The authors declare that they have no financial or other relationships that might lead to a conflict of interest. PRv.D. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis., (© 2019 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Objectives: Insight in the prescribing quality for patients with chronic kidney disease (CKD) in secondary care is limited. The aim of this study is to assess the prescribing quality in secondary care patients with CKD stages 3-5 and possible differences in quality between CKD stages., Design: This was a retrospective cohort study., Setting: Data were collected at two university (n=569 and n=845) and one non-university nephrology outpatient clinic (n=1718) in the Netherlands., Participants: Between March 2015 and August 2016, data were collected from patients with stages 3a-5 CKD seen at the clinics. Blood pressure measurements, laboratory measurements and prescription data were extracted from medical records. For each prescribing quality indicator, patients with incomplete data required for calculation were excluded., Outcome Measures: Potentially appropriate prescribing of antihypertensives, renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, phosphate binders and potentially inappropriate prescribing according to prevailing guidelines was assessed using prescribing quality indicators. Χ 2 or Fisher's exact tests were used to test for differences in prescribing quality., Results: RAAS inhibitors alone or in combination with diuretics (57% or 52%, respectively) and statins (42%) were prescribed less often than phosphate binders (72%) or antihypertensives (94%) when indicated. Active vitamin D was relatively often prescribed when potentially not indicated (19%). Patients with high CKD stages were less likely to receive RAAS inhibitors but more likely to receive statins when indicated than stage 3 CKD patients. They also received more active vitamin D and erythropoietin-stimulating agents when potentially not indicated., Conclusions: Priority areas for improvement of prescribing in CKD outpatients include potential underprescribing of RAAS inhibitors and statins, and potential overprescribing of active vitamin D. CKD stage should be taken into account when assessing prescribing quality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

The increased prevalence of vitamin D [25(OH)D] deficiency in type 1 diabetes mellitus (T1DM) may be related to low insulin levels in the hepatic portal venous system. In this prospective matched-control study, we demonstrate that long-term intraperitoneal insulin does not influence 25(OH)D concentrations in patients with T1DM as compared with subcutaneous insulin administration.

Purpose: Patients with extracorporeal life support (ECLS) are at risk for hemolysis-related complications. Therefore, monitoring of free hemoglobin (fHb) levels is indicated. Conventional methods for fHb are laborious and not always available. Here we evaluated the suitability of the hemolysis-index (H-index), an internal quality control parameter of clinical chemistry platforms, as a clinical parameter for ECLS patients., Materials and Methods: The performance of the H-index assay was evaluated using standard procedures. Furthermore, H-index data from ECLS patients (n = 56) was analyzed retrospectively., Results: The H-index significantly correlated with fHb and showed good analytical performance. During ECLS 19.6% of the patients had an H-index above 20 in at least 2 consecutive blood draws, indicating significant hemolysis. In the patients with clot formation in the pumphead the H-index peaked above 100. Visible clots at other locations did not always coincide with hemolysis. H-index peaks were more prevalent in patients that died during ECLS support., Conclusions: We conclude that the H-index is a suitable and cost-efficient alternative for the conventional fHb analysis with good analytic performance. The H-index aids in the early detection of hemolysis in patients with ECLS. A repeated H-index>20 was a predictor of mortality., (Copyright © 2019. Published by Elsevier Inc.)

Aims: Oxidative stress is a driver in the development of type 2 diabetes (T2DM) complications. As thiols (R-SH) are oxidized by reactive oxygen and sulfur species, circulating concentrations may directly reflect systemic redox status. We hypothesized that high serum R-SH concentrations are a reflection of a favourable redox status and may therefore positively associate with disease status., Methods: R-SH were measured in serum of 943 T2DM outpatients (55% males, 65 years and HbA1c of 6.7% (50 mmol/mol)) with a follow-up period of 1.2 years., Results: In the highest R-SH tertile patients were younger, more often men, had less microvascular complications, lower HbA1c and were more often treated nutritionally or with oral glucose-lowering drugs. Age- and sex adjusted hazard ratios for developing micro-, macro- or any complication plus death were 0.994, 0.992 and 0.993: even after adjustment for potential confounders. The Harrell's C statistic to predict microvascular complications or any complication plus death was higher in the models with R-SH than in those without R-SH., Conclusions: Although R-SH concentrations were associated with a favourable disease status, it did not add to the predictive capacity for long-term complications. Based on the current data R-SH seems unsuitable as a prognostic marker in T2DM.

About 44 surface water samples were collected in the wet and dry seasons around mining areas near the city of Potchefstroom in South Africa, and physicochemical parameters were analyzed to assess the speciation of pollutants and impact on dispersion potential. It was found that concentrations of the trace elements measured decreased significantly during the dry season. High concentrations of trace elements during the wet season were correlated to high effluents from anthropogenic sources which were flowing into the surface water. Aqueous metal speciation in both seasons was conducted using the PHREEQC geochemical modelling code. The seasonal variation of species observed was due to changes in the physicochemical quality of water between the two seasons. Collected data indicated that high percentages of Ca and Mg were present as free hydrate species, whereas the Fe, Cd, As, and U were mostly present as carbonate or hydroxide species.

Background: Aldosterone is elevated in chronic kidney disease (CKD) and may be involved in hypertension. Surprisingly, the determinants of the plasma aldosterone concentration (PAC) and its role in hypertension are not well studied in CKD. Therefore, we studied the determinants of aldosterone and its association with blood pressure in CKD patients. We also studied this during renin-angiotensin-aldosterone system inhibition (RAASi) to establish clinical relevance, as RAASi is the treatment of choice in CKD with albuminuria., Methods: We performed a post-hoc analysis on data from a randomized controlled double blind cross-over trial in non-diabetic CKD patients (n = 33, creatinine clearance (CrCl) 85 (75-95) ml/min, proteinuria 3.2 (2.5-4.0) g/day). Patients were treated with losartan 100 mg (ARB), and ARB + hydrochlorothiazide 25 mg (HCT), during both a regular (200 ± 10 mmol Na + /day) and low (89 ± 8 mmol Na + /day) dietary sodium intake, in 6-week study periods. PAC data at the end of each study period were analyzed. The association between PAC and blood pressure was analyzed continuously, and according to PAC above or below the median., Results: Lower CrCl was correlated with higher PAC during placebo as well as during ARB (β = -1.213, P = 0.008 and β = -1.090, P = 0.010). Higher PAC was not explained by high renin, illustrated by a comparable association between CrCl and the aldosterone-to-renin ratio. The association between lower CrCl and higher PAC was also found in a second study with single RAASi with ACE inhibition (ACEi; lisinopril 40 mg/day), and dual RAASi (lisinopril 40 mg/day + valsartan 320 mg/day). Higher PAC was associated with a higher systolic blood pressure (P = 0.010) during different study periods. Only during maximal treatment with ARB + HCT + dietary sodium restriction, blood pressure was no longer different in subjects with a PAC above and below the median., Conclusions: In CKD patients with a standardized regular sodium intake, worse renal function is associated with a higher aldosterone, untreated and during RAASi with either ARB, ACEi, or both. Furthermore, higher aldosterone is associated with higher blood pressure, which can be treated with the combination of RAASi, HCT and dietary sodium restriction. The first study was performed before it was standard to register trials and the study was not retrospectively registered. The second study was registered in the Netherlands Trial Register on the 5th of May 2006 (NTR675).

Minimal invasive extracorporeal circulation (MiECC) systems have initiated important efforts within science and technology to further improve the biocompatibility of cardiopulmonary bypass components to minimize the adverse effects and improve end-organ protection. The Minimal invasive Extra-Corporeal Technologies international Society was founded to create an international forum for the exchange of ideas on clinical application and research of minimal invasive extracorporeal circulation technology. The present work is a consensus document developed to standardize the terminology and the definition of minimal invasive extracorporeal circulation technology as well as to provide recommendations for the clinical practice. The goal of this manuscript is to promote the use of MiECC systems into clinical practice as a multidisciplinary strategy involving cardiac surgeons, anaesthesiologists and perfusionists., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Urinary excretion of alpha-1-microglobulin and beta-2-microglobulin reflects tubular damage and predicts outcome in patients with idiopathic membranous nephropathy with reasonable accuracy. Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are novel biomarkers of tubular damage. We investigated if these markers could improve prediction of outcome in idiopathic membranous nephropathy., Methods: We measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in urine samples from patients with idiopathic membranous nephropathy, who had nephrotic proteinuria and normal renal function. Excretion of alpha-1-microglobulin and beta-2-microglobulin had been measured previously. Progression was defined as a serum creatinine rise >30%, a rise in serum creatinine to an absolute value of ≥135 µmol/L, or a clinical decision to start immunosuppressive therapy. Remission was defined as proteinuria <3.5 g/day and >50% reduction from baseline., Results: Sixty-nine patients were included. Median follow-up was 35 months (interquartile range 18-63 months). Progression occurred in 30 patients (44%), and spontaneous remission in 36 (52%). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates were significantly correlated with each other, and with alpha-1-microglobulin and beta-2-microglobulin. The areas under the receiver operating characteristic curves for progression were 0.75 (0.62-0.87) for kidney injury molecule-1 and 0.74 (0.62-0.87) for neutrophil gelatinase-associated lipocalin. In multivariate analysis with either alpha-1-microglobulin and beta-2-microglobulin, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not independently predict outcome., Conclusion: Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates correlated with excretion rates of other tubular damage markers and predicted outcome in patients with idiopathic membranous nephropathy. They did not add prognostic value compared to measurement of either alpha-1-microglobulin or beta-2-microglobulin., (© The Author(s) 2015.)

Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating evidence now suggests that these patients are more prone to developing renal failure later in life. We therefore sought to investigate to what extent renal functional changes, inflammation and collagen deposition are reversible after cessation of disease induction, potentially explaining residual sensitivity to damage. Using a rat model of Angiotensin II (Ang II)-induced hypertensive renal disease we show the development of severe hypertension (212 ± 10.43 vs. 146 ± 1.4 mmHg, p<0.001) and proteinuria (51.4 ± 6.3 vs. 14.7 ± 2.0 mg/24h, p<0.01) with declined creatinine clearance (2.0 ± 0.5 vs. 4.9 ± 0.6 mL/min, p<0.001) to occur after 3 weeks of Ang II infusion. At the structural level, Ang II infusion resulted in interstitial inflammation (18.8 ± 4.8 vs. 3.6 ± 0.5 number of macrophages, p<0.001), renal interstitial collagen deposition and lymphangiogenesis (4.1 ± 0.4 vs. 2.2 ± 0.4 number of lymph vessels, p<0.01). Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values. However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated. These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage.

Background: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect., Study Design: Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition., Setting & Participants: 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50±13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min)., Predictor: Plasma carboxy-terminal FGF-23 levels., Outcomes: Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period., Results: Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized β=-0.46; P=0.001; model R(2)=0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized β=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment., Limitations: Observational study, limited sample size., Conclusions: FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-23-lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic congestive heart failure (HF) has a rising prevalence and increasing impact on health care systems. Current treatment consists of diuretics, renin-angiotensin-aldosterone system blockers, and restriction of salt and fluids. This strategy is often hampered by a drop in effective circulating volume and hence renal perfusion and function, triggering harmful counter regulatory mechanisms. Slow ultrafiltration by peritoneal dialysis (PD) might be an effective treatment strategy to relieve fluid overload without compromising cardiac output and thereby renal function. In this review, we discuss the (patho)physiological mechanisms of the cardiorenal interaction and the current literature on PD strategies in congestive HF.

Objective: Sodium restriction potentiates the efficacy of the rennin-angiotensin-aldosterone system (RAAS)-blockade and improves long-term cardiovascular and renal protection, even independent of the better blood pressure control. The mechanisms underlying the potentiation of cardiorenal protection by sodium restriction are incompletely understood. RAAS-blockade with angiotensin-converting enzyme (ACE) inhibitors increases circulating levels of the anti-inflammatory and antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is assumed to contribute to its therapeutic effects. We hypothesized that sodium restriction on top of RAAS-blockade further increases AcSDKP, as a possible explanation for the enhanced effects of RAAS-blockade during sodium restriction., Methods: To test this hypothesis, we performed a secondary analysis of a randomized clinical trial investigating 46 nondiabetic chronic kidney disease (CKD) patients (age 50±13 years, 80% men) with overt proteinuria and mild to moderate renal insufficiency. Patients were subjected, in a crossover design, to four double-blind 6-week study periods with either regular sodium diet (194±49 mmol Naday) or low sodium diet (102±52 mmol Na/day) on top of either lisinopril (40 mg/day; single RAAS-blockade) or lisinopril plus valsartan (320 mg/day; dual RAAS-blockade)., Results: Sodium restriction significantly increased circulating levels of AcSDKP during single and dual RAAS-blockade (P=0.032 and 0.042, respectively). Linear mixed-model analysis confirmed that AcSDKP levels were increased in response to sodium restriction, irrespective of sex, age, creatinine clearance, blood pressure, BMI, single or dual RAAS-blockade, treatment sequence and other dietary factors, that is calcium and protein (P=0.020)., Conclusion: In patients with nondiabetic CKD, we demonstrated that sodium restriction, on top of single and dual RAAS-blockade, increases circulating levels of the anti-inflammatory and antifibrotic peptide AcSDKP. The rise in AcSDKP may contribute to the increased protection of RAAS-blockade during sodium restriction.

Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and development of end-stage renal disease (ESRD) remain major concerns in diabetes. In addition, diabetic patients with microalbuminuria have an increased cardiovascular mortality. Therefore, new treatment modalities or strategies are needed to prevent or slow the progression of diabetic nephropathy and prevent cardiovascular disease in diabetes. In this review we describe current concepts in pathophysiology, treatment goals and we discuss future developments in the treatment of diabetic nephropathy. Common risk factors for diabetic nephropathy and its progression are longer duration, poor glycaemic control, hypertension and the presence of albuminuria. Available treatment options, especially renin-angiotensin aldosterone system (RAAS) blockade, but also better blood pressure and blood glucose control, decrease the incidence of cardiovascular disease and renal disease in diabetes. It is important that treatment goals are tailored to the individual patient with individual treatment goals of glycaemic control and blood pressure, depending on age, type of diabetes and diabetes duration. Aggressive treatment of glucose control and blood pressure might not always be best practice for every patient. Since the proportion of ESRD due to diabetic nephropathy remains high, optimisation of RAAS blockade is advocated and can be achieved by adequate sodium restriction and/or diuretic treatment. Moreover, aldosterone blockade might be a valuable strategy, which has potency to slow the progression of diabetic renal disease. Other possible future interventions are under investigation, but large clinical trials have to be awaited to confirm the safety and efficacy of these drugs.

Objective: LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin-kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction., Methods: Thirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m(2), proteinuria 1.9 [0.9-3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 ± 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 ± 52 mmol Na(+)/day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3-1.1] g/day (P < 0.001)., Results: Plasma PCSK9 was increased at baseline in proteinuric subjects (213 [161-314] vs. 143 [113-190] ug/L in controls, P ≤ 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline (R = 0.399, P = 0.018) and at maximal antiproteinuric treatment (R = 0.525, P = 0.001), but did not decrease during proteinuria reduction (P = 0.84). Individual changes in total cholesterol (R = 0.365, P = 0.024), non-HDL cholesterol (R = 0.333, P = 0.041), and LDL cholesterol (R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment (P = 0.04)., Conclusion: Plasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Chronic kidney disease (CKD) typically extends over decades. Longitudinal monitoring of kidney function in CKD is thus of great importance. Here, we retrospectively evaluate use of the Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations to monitor long-term course of kidney function and to identify individuals with progressive kidney function loss., Methods: Patients were selected from our outpatient clinic for having four glomerular filtration rate measurements (mGFR, (125)I-iothalamate) and at least ≥ 4 years of follow-up. Renal function slopes were obtained by within-individual linear regression., Results: Sixty-five nondiabetic CKD patients (40 male, mean baseline age 44 ± 12 years) with a median (range) of 9 (4-16) mGFR measurements and a median follow-up of 11 (4-33) years were included. Both equations significantly underestimated mGFR/(BSA) at baseline and at the end of follow-up. mGFR slope was significantly underestimated by the MDRD study but not by CKD-EPI equation (slopes -1.41 ± 2.06, -1.07 ± 1.72 and -1.39 ± 1.77 mL/min/1.73 m(2)/year, respectively). Sensitivity and specificity to identify progressive kidney function loss (mGFR/(BSA) slope > 1.5 mL/min/1.73 m(2)/ year, n = 23) were 78 and 88% for the MDRD study and 91 and 80% for CKD-EPI equation. In the subgroup of progressors, both MDRD study and CKD-EPI equation underestimated the rate of mGFR loss (P < 0.05), Conclusions: Long-term course of mGFR is reasonably well estimated by CKD-EPI and slightly underestimated by MDRD study equation. Patients with progressive kidney function loss may, however, not be reliably identified, so caution is warranted when using these equations in clinical practice.

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: Overt proteinuria is a strong risk factor for thromboembolism, owing to changes in the levels of various coagulation proteins and urinary antithrombin loss. The described coagulation disturbances in these patients are based on outdated studies conducted primarily in the 1970s and 1980s. Whether these coagulation disturbances resolve with antiproteinuric therapy has yet to be studied., Methods: A total of 32 patients with overt proteinuria (median, 3.7 g day(-1) ; interquartile range, 1.5-5.6) were enrolled in this intervention crossover trial designed to assess optimal antiproteinuric therapy with sodium restriction, losartan, and diuretics. Levels of various procoagulant and anticoagulant proteins, and parameters of two thrombin generation assays (calibrated automated thrombogram [CAT] and prothrombin fragment 1 + 2) were compared between the placebo period and the maximum antiproteinuric treatment period. As a secondary analysis, coagulation measurements of the placebo period in these patients were compared with those of 32 age-matched and sex-matched healthy controls., Results: Median proteinuria was significantly lower during the maximum treatment period (median, 0.9 g day(-1) ; interquartile range, 0.6-1.4; P < 0.001) than during the placebo period. Similarly, levels of various liver-synthesized procoagulant and anticoagulant proteins, activated protein C resistance and prothrombin fragment 1 + 2 levels were significantly lower during the maximum treatment period than during the placebo period. However, von Willebrand factor and factor VIII levels were similar. On the basis of the higher levels of procoagulant proteins (fibrinogen, FV, FVIII, and von Willebrand factor) and both thrombin generation assays, patients were substantially more prothrombotic than healthy controls (P < 0.004)., Conclusions:  Antiproteinuric therapy ameliorates the prothrombotic state. Proteinuric patients are in a more prothrombotic state than healthy controls., (© 2011 International Society on Thrombosis and Haemostasis.)

Background: The variable course of immunoglobulin A nephropathy (IgAN) warrants accurate tools for the prediction of progression. Urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are markers for the detection of early tubular damage caused by various renal conditions. We evaluated the prognostic value of these markers in patients with IgAN., Methods: We included patients (n = 65, 72% male, age 43 ± 13 years) with biopsy-proven IgAN, who were evaluated for proteinuria. Urinary KIM-1 and NGAL were measured by enzyme-linked immunosorbent assay. We analysed data using Cox regression for the outcome end-stage renal disease (ESRD)., Results: Median serum creatinine was 142 μmol/L and proteinuria 2.2 g/day. During follow-up (median 75 months), 23 patients (35%) developed ESRD. In patients with IgAN median urinary KIM-1 excretion was 1.7 ng/min and NGAL excretion was 47 ng/min, both significantly higher than in healthy controls. KIM-1 and NGAL were correlated with proteinuria (r = 0.40 and 0.34, respectively, P < 0.01) and each other (r = 0.53, P < 0.01) but not with estimated glomerular filtration rate (eGFR). Interestingly, KIM-1 was not significantly correlated with the excretion of α(1)-microglobulin (α(1)m) and β(2)-microglobulin (β(2)m), known markers of tubular injury. Univariate analysis showed that baseline serum creatinine and urinary excretion of total protein, α(1)m, β(2)m, immunoglobulin G, KIM-1 and NGAL were significantly associated with ESRD. By multivariate analysis, serum creatinine and KIM-1 excretion proved to be significant independent predictors of ESRD., Conclusion: KIM-1 and NGAL excretion are increased in patients with IgAN and correlate with proteinuria but not with eGFR. Baseline serum creatinine and urinary KIM-1, but not proteinuria, are independent predictors of ESRD.

Aldosterone, a steroid hormone with mineralocorticoid activity, is far more than merely a salt-and-water hormone. Aldosterone has a number of non-classical, mineralocorticoid receptor (MR)-mediated actions, including tissue remodeling, modulation of vascular tone and stimulating inflammation and fibrosis, which may fuel progression of end organ damage. Aldosterone breakthrough during blockade of the renin-angiotensin aldosterone system (RAAS) may explain why this treatment regimen only confers partial cardiovascular and renal protection. Of major interest, aldosterone is deleterious only if inappropriately high for its sodium status i.e. high aldosterone and high sodium. The mechanism of sodium dependence of aldosterone-induced renal and cardiovascular damage continues to fascinate. Aldosterone excess increases sodium and fluid retention and consequently increases blood pressure, which, in turn, mediates target organ damage. Moreover, blood pressure independent effects play a role with dissociation of low circulating and high tissue aldosterone levels during high sodium intake and possibly enhanced MR signaling. MR blockade is a valuable strategy, which has potency to halt the progressive end organ damage as observed during current treatments. In heart failure, MR blockade on top of RAAS blockade reduces hard clinical endpoints. Despite encouraging results on the intermediate endpoint proteinuria, long-term data on the efficacy and safety of MR blockade in preventing dialysis and/or cardiovascular endpoints in chronic kidney disease are still lacking. It is obligatory that future clinical studies on the effects of MR blockade on end-organ damage take into account the sodium status.

Background and Objectives: Connective tissue growth factor (CTGF/CCN-2) is a key player in fibrosis. Plasma CTGF levels predict end-stage renal disease and mortality in diabetic chronic kidney disease (CKD), supporting roles in intra- and extrarenal fibrosis. Few data are available on CTGF in nondiabetic CKD. We investigated CTGF levels and effects of antiproteinuric interventions in nondiabetic proteinuric CKD., Design, Setting, Participants, & Measurements: In a crossover randomized controlled trial, 33 nondiabetic CKD patients (3.2 [2.5 to 4.0] g/24 h proteinuria) were treated during 6-week periods with placebo, ARB (100 mg/d losartan), and ARB plus diuretics (100 mg/d losartan plus 25 mg/d hydrochlorothiazide) combined with consecutively regular and low sodium diets (193 ± 62 versus 93 ± 52 mmol Na(+)/d)., Results: CTGF was elevated in plasma (464 [387 to 556] pmol/L) and urine (205 [135 to 311] pmol/24 h) of patients compared with healthy controls (n = 21; 96 [86 to 108] pmol/L and 73 [55 to 98] pmol/24 h). Urinary CTGF was lowered by antiproteinuric intervention, in proportion to the reduction of proteinuria, with normalization during triple therapy (CTGF 99 [67 to 146] in CKD versus 73 [55 to 98] pmol/24 h in controls). In contrast, plasma CTGF was not affected., Conclusions: Urinary and plasma CTGF are elevated in nondiabetic CKD. Only urinary CTGF is normalized by antiproteinuric intervention, consistent with amelioration of tubular dysfunction. The lack of effect on plasma CTGF suggests that its driving force might be independent of proteinuria and that short-term antiproteinuric interventions are not sufficient to correct the systemic profibrotic state in CKD.

Objective: To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose., Design: Multicentre crossover randomised controlled trial., Setting: Outpatient clinics in the Netherlands., Participants: 52 patients with non-diabetic nephropathy., Interventions: All patients were treated during four 6 week periods, in random order, with angiotensin receptor blockade (valsartan 320 mg/day) or placebo, each combined with, consecutively, a low sodium diet (target 50 mmol Na(+)/day) and a regular sodium diet (target 200 mmol Na(+)/day), with a background of ACE inhibition (lisinopril 40 mg/day) during the entire study. The drug interventions were double blind; the dietary interventions were open label., Main Outcome Measures: The primary outcome measure was proteinuria; the secondary outcome measure was blood pressure., Results: Mean urinary sodium excretion, a measure of dietary sodium intake, was 106 (SE 5) mmol Na(+)/day during a low sodium diet and 184 (6) mmol Na(+)/day during a regular sodium diet (P<0.001). Geometric mean residual proteinuria was 1.68 (95% confidence interval 1.31 to 2.14) g/day during ACE inhibition plus a regular sodium diet. Addition of angiotensin receptor blockade to ACE inhibition reduced proteinuria to 1.44 (1.07 to 1.93) g/day (P=0.003), addition of a low sodium diet reduced it to 0.85 (0.66 to 1.10) g/day (P<0.001), and addition of angiotensin receptor blockade plus a low sodium diet reduced it to 0.67 (0.50 to 0.91) g/day (P<0.001). The reduction of proteinuria by the addition of a low sodium diet to ACE inhibition (51%, 95% confidence interval 43% to 58%) was significantly larger (P<0.001) than the reduction of proteinuria by the addition of angiotensin receptor blockade to ACE inhibition (21%, (8% to 32%) and was comparable (P=0.009, not significant after Bonferroni correction) to the reduction of proteinuria by the addition of both angiotensin receptor blockade and a low sodium diet to ACE inhibition (62%, 53% to 70%). Mean systolic blood pressure was 134 (3) mm Hg during ACE inhibition plus a regular sodium diet. Mean systolic blood pressure was not significantly altered by the addition of angiotensin receptor blockade (131 (3) mm Hg; P=0.12) but was reduced by the addition of a low sodium diet (123 (2) mm Hg; P<0.001) and angiotensin receptor blockade plus a low sodium diet (121 (3) mm Hg; P<0.001) to ACE inhibition. The reduction of systolic blood pressure by the addition of a low sodium diet (7% (SE 1%)) was significantly larger (P=0.003) than the reduction of systolic blood pressure by the addition of angiotensin receptor blockade (2% (1)) and was similar (P=0.14) to the reduction of systolic blood pressure by the addition of both angiotensin receptor blockade and low sodium diet (9% (1)), to ACE inhibition., Conclusions: Dietary sodium restriction to a level recommended in guidelines was more effective than dual blockade for reduction of proteinuria and blood pressure in non-diabetic nephropathy. The findings support the combined endeavours of patients and health professionals to reduce sodium intake. Trial registration Netherlands Trial Register NTR675.