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Background and Aims There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins neutrophil-gelatinase-associated lipocalin (NGAL), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases 2 (TIMP2), kidney injury molecule-1 (KIM-1), C-X-C motif chemokine 9 (CXCL9), transforming growth factor-beta 1 (TGF-β1), solute carrier family 22 member 2 (SLC22A2), nephrin, cubilin, and uromodulin (UMOD) have been proposed as early kidney injury biomarkers. To guide clinical interpretation, their urinary concentrations should be accompanied by reference intervals, which we here establish in a representative Dutch middle-aged population. Materials and Methods The 24 h urine samples from 1443 Caucasian middle-aged men and women were analyzed for the biomarkers by quantitative LC-MS/MS. Biomarker excretion per 24 h were calculated, and urine creatinine and osmolality were measured for dilution normalization. This population was characterized by demographic and anthropometric parameters, comorbid conditions, and conventional kidney function measures. Results NGAL, IGFBP7, TIMP2, KIM-1, and UMOD could be quantified in this population, whereas nephrin, SLC22A2, and CXCL9 were below their detection limits. Urine creatinine and osmolality were correlated to urine volume (r = −0.71; −0.74) and to IGFBP7 (r = 0.73; 0.71) and TIMP2 (r = 0.71; 0.69). Crude and normalized biomarker concentrations were affected by sex, but not by age, body mass index, smoking, kidney function, or common comorbid conditions. The reference intervals (men; women) were 18–108; 21–131 pmol IGFBP7/mmol creatinine, 1–63; 4–224 pmol NGAL/mmol creatinine, 7–48; 7–59 pmol TIMP2/mmol creatinine, Conclusion We present dilution-normalized and sex-stratified urinary reference intervals of kidney injury biomarkers in a middle-aged Caucasian population.

Peer reviewed: True, Funder: University of New South Wales; FundRef: http://dx.doi.org/10.13039/501100001773, OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate

Background: We recently showed that seasonal patterns of COVID-19 incidence and Influenza-Like Illnesses incidence are highly similar, in a country in the temperate climate zone, such as the Netherlands. We hypothesize that in The Netherlands the same environmental factors and mobility trends that are associated with the seasonality of flu-like illnesses are predictors of COVID-19 seasonality as well. Methods: We used meteorological, pollen/hay fever and mobility data from the Netherlands. For the reproduction number of COVID-19 (Rt), we used daily estimates from the Dutch State Institute for Public Health. For all datasets, we selected the overlapping period of COVID-19 and the first allergy season: from February 17, 2020 till September 21, 2020 (n = 218). Backward stepwise multiple linear regression was used to develop an environmental prediction model of the Rt of COVID-19. Next, we studied whether adding mobility trends to an environmental model improved thepredictive power. Results: Through stepwise backward multiple linear regression four highly significant (p < 0.01) predictive factors are selected in our combined model: temperature, solar radiation, hay fever incidence, and mobility to indoor recreation locations. Our combined model explains 87.5% of the variance of Rt of COVID-19 and has a good and highly significant fit: F(4, 213) = 374.2, p < 0.00001. This model had a better overall predictive performance than a solely environmental model, which explains 77.3% of the variance of Rt (F(4, 213) = 181.3, p < 0.00001). Conclusions: We conclude that the combined mobility and environmental model can adequately predict the seasonality of COVID-19 in a country with a temperate climate like the Netherlands. In this model higher solar radiation, higher temperature and hay fever are related to lower COVID-19 reproduction, and higher mobility to indoor recreation locations is related to an increased COVID-19 spread.

Background and aims: Age-related kidney function decline is accelerated in patients with coronary heart disease (CHD). CHD and chronic kidney disease may share common etiologies. We examined plasma fatty acids (FAs) as novel biomarkers of kidney function decline after myocardial infarction (MI). Methods and results: The analysis included 2329 Dutch post–MI patients aged 60-80y (Alpha Omega Cohort) most receiving state-of-the-art medications. Plasma FAs (% total FAs) in cholesteryl esters were assessed at baseline (2002–2006), and ∼40 months change in creatinine-cystatin C based glomerular filtration rate was estimated (eGFR, in ml/min per 1.73 m2). Beta coefficients for annual eGFR change in relation to plasma linoleic acid (LA; 50.1% of total FAs in CE), omega-3 FAs (EPA + DHA; 1.7%), odd-chain FAs (C15:0 and C17:0; 0.2%), and C14:0 (0.7%) were obtained from linear regression analyses adjusted for age, sex, smoking, and alcohol intake. Mean baseline eGFR ±SD was 78.5 ± 18.7, which declined by 4.7 ± 13.1 during follow-up, or 1.4 ± 3.9 per year. The annual decline in eGFR was less in patients with higher plasma LA (adjusted beta: 0.40 for LA >47 vs ≤ 47%, 95% CI: 0.01; 0.78; p = 0.046). Associations of plasma LA with annual eGFR decline were stronger in 437 patients with diabetes (1.21, 0.24; 2.19) and in 402 patients with CKD (eGFR

Objective: To investigate the impact of the coronavirus pandemic on mental health in hemodialysis patients, we assessed depression, anxiety and quality of life with valid mental health measures before and after the start of the pandemic. Methods: Data were used from 121 hemodialysis patients from the ongoing prospective multicenter DIVERS-II study. COVID-19 related stress was measured with the Perceived Stress Scale – 10, depression with the Beck Depression Inventory – second edition (BDI-II)), anxiety with the Beck Anxiety Inventory (BAI) and quality of life with the Short Form – 12 (SF-12). Scores during the first and second COVID-19 wave in the Netherlands were compared to data prior to the pandemic with linear mixed models. Results: No significant differences were found in BDI-II, BAI and SF-12 scores between before and during the pandemic. During the first wave, 33% of participants reported COVID-19 related stress and in the second wave 37%. These patients had higher stress levels (mean difference (MD) 4.7 (95%CI 1.5; 8.0), p = 0.005) and BDI-II scores (MD 4.9 (95%CI 0.7; 9.0), p = 0.021) and lower SF-12 mental component summary scores (MD -5.3 (95%CI -9.0, −1.6), p = 0.006) than patients who did not experienced COVID-19 stress. These differences were already present before the pandemic. Conclusion: The COVID-19 pandemic does not seem to influence mental health in hemodialysis patients. However, a substantial subgroup of patients with pre-existent mental health problems may be more susceptible to experience COVID-19 related stress.

Objective: To investigate the effectiveness of a guided internet-based self-help intervention for hemodialysis patients with depressive symptoms. Method: Chronic hemodialysis patients from nine Dutch hospitals with a depression score on the Beck Depression Inventory – second edition (BDI-II) of ≥10, were cluster-randomized into a five modules guided internet-based self-help problem solving therapy intervention or a parallel care-as-usual control group. Clusters were based on hemodialysis shift. The primary outcome depression was measured with the BDI-II. Analysis was performed with linear mixed models. Results: A total of 190 hemodialysis patients were cluster-randomized to the intervention (n = 89) or control group (n = 101). Post-intervention measurement was completed by 127 patients (67%) and more than half of the patients (54%) completed the intervention. No significant differences were found on the BDI-II score between the groups (mean difference − 0.1, 95%CI -3.0; 2.7, p = 0.94). Per protocol sensitivity analysis showed comparable results. No significant differences in secondary outcomes were observed between groups. Conclusions: Guided internet-based self-help problem solving therapy for hemodialysis patients with depressive symptoms does not seem to be effective in reducing these symptoms as compared to usual care. Future research should examine how to best design content and accessibility of an intervention for depressive symptoms in hemodialysis patients. Trial registration: Dutch Trial Register: Trial NL6648 (NTR6834) (prospectively registered 13th November 2017).

Background During the first wave of COVID-19 it was hypothesized that COVID-19 is subject to multi-wave seasonality, similar to Influenza-Like Illnesses since time immemorial. One year into the pandemic, we aimed to test the seasonality hypothesis for COVID-19. Methods We calculated the average annual time-series for Influenza-Like Illnesses based on incidence data from 2016 till 2019 in the Netherlands, and compared these with two COVID-19 time-series during 2020/2021 for the Netherlands. We plotted the time-series on a standardized logarithmic infection scale. Finally, we calculated correlation coefficients and used univariate regression analysis to estimate the strength of the association between the time-series of COVID-19 and Influenza-Like Illnesses. Results The time-series for COVID-19 and Influenza-Like Illnesses were strongly and highly significantly correlated. The COVID-19 peaks were all during flu season, and lows were all in the opposing period. Finally, COVID-19 meets the multi-wave characteristics of earlier flu-like pandemics, namely a short first wave at the tail-end of a flu season, and a longer and more intense second wave during the subsequent flu season. Conclusions We conclude that seasonal patterns of COVID-19 incidence and Influenza-Like Illnesses incidence are highly similar, in a country in the temperate climate zone, such as the Netherlands. Further, the COVID-19 pandemic satisfies the criteria of earlier respiratory pandemics, namely a first wave that is short-lived at the tail-end of flu season, and a second wave that is longer and more severe. This seems to imply that the same factors that are driving the seasonality of Influenza-Like Illnesses are causing COVID-19 seasonality as well, such as solar radiation (UV), temperature, relative humidity, and subsequently seasonal allergens and allergies., Highlights • Time-series of COVID-19 and Influenza-Like illnesses have highly similar seasonal patterns in the Netherlands. • COVID-19 satisfies the seasonal criteria of earlier flu-like pandemics. • The implication is that the seasonal factors driving flu season, are also responsible for COVID-19 seasonality. • Determined seasonality by applying comparative time-series analysis and a standardized logarithmic infection scale.

Background Itching (pruritus) is common in dialysis patients, but little is known about its impact on health-related quality of life (HRQOL), sleep problems and psychological symptoms. This study investigates the impact of itching in dialysis patients by looking into the persistence of itching, the effect of itching on the course of HRQOL and the combined effect of itching with sleep problems and with psychological symptoms on HRQOL. Methods Data were obtained from the RENINE/PROMs registry and included 2978 dialysis patients who completed patient-reported outcome measures between 2018 and 2020. Itching, sleep problems and psychological symptoms were assessed with the Dialysis Symptom Index (DSI) and HRQOL with the 12-item Short Form Health Survey. Effects of itching on HRQOL and interactions with sleep problems and psychological symptoms were investigated cross-sectionally and longitudinally using linear regression and linear mixed models. Results Half of the patients experienced itching and in 70% of them, itching was persistent. Itching was associated with a lower physical and mental HRQOL {−3.35 [95% confidence interval (CI) −4.12 to −2.59) and −3.79 [95% CI −4.56 to −3.03]}. HRQOL remained stable during 2 years and trajectories did not differ between patients with or without itching. Sleep problems (70% versus 52%) and psychological symptoms (36% versus 19%) were more common in patients with itching. These symptoms had an additional negative effect on HRQOL but did not interact with itching. Conclusions The persistence of itching, its impact on HRQOL over time and the additional effect on HRQOL of sleep problems and psychological symptoms emphasize the need for recognition and effective treatment of itching to reduce symptom burden and improve HRQOL.

BackgroundWe recently showed that seasonal patterns of COVID-19 incidence and Influenza-Like Illnesses incidence are highly similar, in a country in the temperate climate zone, such as the Netherlands (latitude: 52°N). We hypothesize that in The Netherlands the same environmental factors and mobility trends that are associated with the seasonality of flu-like illnesses are predictors of COVID-19 seasonality as well.MethodsWe used meteorological, pollen/hay fever and mobility data from the Netherlands with its 17.4 million inhabitants. For the reproduction number of COVID-19 (Rt), we used data from the Dutch State Institute for Public Health. This Rt metric is a daily estimate that is based on positive COVID-19 tests in the Netherlands in hospitals and municipalities. For all datasets we selected the overlapping period of COVID-19 and the first allergy season: from February 17, 2020 till September 21, 2020 (total number of measurements: n = 218), the end of pollen season. Backward stepwise multiple linear regression was used to develop an environmental prediction model of the Rt of COVID-19. Next, we studied whether adding mobility trends to an environmental model improved the predictive power.ResultsBy means of stepwise backward multiple linear regression four highly significant (p value < 0.01) predictive factors are selected in our combined model: temperature, solar radiation, hay fever incidence, and mobility to indoor recreation locations. Our combined model explains 87.5% of the variance of Rt of COVID-19 and has a good and highly significant fit: F(4, 213) = 374.2, p-value < 0.00001. The combined model had a better overall predictive performance compared to a solely environmental model, which still explains 77.3% of the variance of Rt, and a good and highly significant fit: F(4, 213) = 181.3, p < 0.00001.ConclusionsWe conclude that the combined mobility and environmental model can adequately predict the seasonality of COVID-19 in a country with a temperate climate like the Netherlands. In this model higher solar radiation, higher temperature and hay fever are related to lower COVID-19 reproduction, and mobility to indoor recreation locations with increased COVID-19 spread.HighlightsThe seasonality of COVID-19 can be well-explained by environmental factors and mobility.A combined model explains 87.5% of the variance of the reproduction number of COVID-19Inhibitors of the reproduction number of COVID-19 are higher solar radiation, and seasonal allergens/allergies.Mobility, especially to indoor recreation locations, increases the reproduction number of COVID-19.Temperature has no direct effect on the reproduction number of COVID-19, but affects mobility and seasonal allergens.Adding mobility trends to an environmental model improves the predictive value regarding the reproduction number of COVID-19.

Background Post-myocardial infarction (MI) patients have a doubled rate of kidney function decline compared with the general population. We investigated the extent to which high intake of total, animal and plant protein are risk factors for accelerated kidney function decline in older stable post-MI patients. Methods We analysed 2255 post-MI patients (aged 60–80 years, 80% men) of the Alpha Omega Cohort. Dietary data were collected with a biomarker-validated 203-item food frequency questionnaire. At baseline and 41 months, we estimated glomerular filtration rate based on the Chronic Kidney Disease Epidemiology Collaboration equations for serum cystatin C [estimated glomerular filtration rate (eGFRcysC)] alone and both creatinine and cystatin C (eGFRcr–cysC). Results Mean [standard deviation (SD)] baseline eGFRcysC and eGFRcr–cysC were 82 (20) and 79 (19) mL/min/1.73 m2. Of all patients, 16% were current smokers and 19% had diabetes. Mean (SD) total protein intake was 71 (19) g/day, of which two-thirds was animal and one-third plant protein. After multivariable adjustment, including age, sex, total energy intake, smoking, diabetes, systolic blood pressure, renin–angiotensin system blocking drugs and fat intake, each incremental total daily protein intake of 0.1 g/kg ideal body weight was associated with an additional annual eGFRcysC decline of −0.12 (95% confidence interval −0.19 to −0.04) mL/min/1.73 m2, and was similar for animal and plant protein. Patients with a daily total protein intake of ≥1.20 compared with Conclusion A higher protein intake was significantly associated with a more rapid kidney function decline in post-MI patients.

Background and Aims The number of older (≥65y) people with ESKD starting chronic dialysis increased substantially the past decade because of ageing of the population due to improved health care. In addition, older age is no longer a contraindication for dialysis. Finally, older individuals are more often ineligible for kidney transplantation. Many older people with stage 5 CKD non-dialysis have a low health-related quality of life (HRQOL) and high symptom burden. In this group, improving HRQOL and lowering symptom burden may be deemed more important than solely the prolongation of life. Little is known about the effect of dialysis treatment on HRQOL and symptom burden. Therefore, we investigated the evolution of HRQOL and symptoms before and after the start of dialysis in older ESKD patients. Method The European Quality (EQUAL) study is an ongoing European prospective multi-center follow-up study in late stage 4/5 CKD patients aged ≥65 years. For the present analyses, we included all patients who started dialysis. HRQOL was assessed every 3-6 months using the RAND-36 questionnaire, resulting in a physical component summary (PCS) and a mental component summary (MCS) score. Component scores ranged from 0-100 with higher scores indicating a better HRQOL. Kidney disease-related symptom burden was assessed every 3-6 months using the dialysis symptom index (DSI). The sum score for symptom number ranged from 0 to 30 and for symptom severity from 0 to 150, with higher scores indicating a higher symptom burden. We used linear mixed models (LMM) to explore the evolution of mental and physical HRQOL, symptom number and symptom severity during the year preceding and following dialysis initiation. Results In total, 571 older dialysis patients were included. At baseline (dialysis initiation), mean (SD) age was 76 (6) years, 74% were men, 47% had diabetes, 9% were current smokers, 34% had cardiovascular disease and the mean (SD) residual kidney function was 8.6 (4.4) ml/min/1.73m2. Mean (SD) MSC was 55 (23), PSC was 43 (21), and the number of symptoms was 15 (7) with a symptom severity of 88 (18). Overall, LMM showed that in the year preceding dialysis MCS decreased by 15.7 (95% CI: 11.9 to 19.5), PCS decreased by 12.0 (8.2 to 15.7), symptom number increased by 3.5 (2.5 to 4.6) and symptom severity increased by 5.3 (1.8 to 8.8). In the year following dialysis, MCS increased by 1.9 (-2.7 to 6.5), PCS decreased by 2.1 (-6.9 to 2.8), symptom number decreased by 0.9 (-0.3 to 2.1) and symptom severity decreased by 7.6 (2.8 to 12.4). Conclusion Both mental and physical HRQOL, as well as symptom number and severity, worsened considerably during the year preceding dialysis, but stabilized after dialysis initiation. These results could aid nephrologists in informing older ESKD patients who consider starting dialysis and improve the shared decision making process.

Current models for flu-like epidemics insufficiently explain multi-cycle seasonality. Meteorological factors alone, including the associated behavior, do not predict seasonality, given substantial climate differences between countries that are subject to flu-like epidemics or COVID-19. Pollen is documented to be allergenic, it plays a role in immuno-activation and defense against respiratory viruses, and seems to create a bio-aerosol that lowers the reproduction number of flu-like viruses. Therefore, we hypothesize that pollen may explain the seasonality of flu-like epidemics, including COVID-19, in combination with meteorological variables. We have tested the Pollen-Flu Seasonality Theory for 2016–2020 flu-like seasons, including COVID-19, in the Netherlands, with its 17.4 million inhabitants. We combined changes in flu-like incidence per 100 K/Dutch residents (code: ILI) with pollen concentrations and meteorological data. Finally, a predictive model was tested using pollen and meteorological threshold values, inversely correlated to flu-like incidence. We found a highly significant inverse correlation of r(224) = −0.41 (p, Graphical abstract Unlabelled Image, Highlights • Testing pollen-flu seasonality theory for 2016–2020 in the Netherlands, overlapping COVID-19 • Pollen have allergenic and immuno-activating properties. • Highly significant inverse correlation between pollen and flu-like incidence. • Solar radiation is a co-inhibitor of flu-like epidemics. • COVID-19 does not break with seasonality pattern, but more data are needed for conclusion.

Acute kidney injury (AKI) is an important risk factor for chronic kidney disease, renal replacement therapy (RRT), and mortality. However, predicting AKI with currently available markers remains problematic. We assessed the predictive value of urinary tissue inhibitor of metalloprotease-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) regarding the need for RRT, and 30-day mortality, in elective cardiac surgery patients. In 344 elective cardiac surgery patients, we measured urinary TIMP-2 and IGFBP7 and serum creatinine at baseline and directly after surgery. Discrimination of both urinary biomarkers was assessed by the C-statistic. Model improvement for each biomarker when added to a basic model containing serum creatinine and duration of surgery was tested by the net-reclassification index (cf-NRI) and integrated discrimination index (IDI). At baseline, mean age was 66 years and 67% were men. Of all patients, 22 required RRT following surgery. IGFBP7 pre- and post-surgery and change in TIMP-2 during surgery predicted RRT with a C-statistic of about 0.80. However, a simple model including baseline serum creatinine and duration of surgery had a C-statistic of 0.92, which was improved to 0.93 upon addition of post-surgery TIMP-2 or IGFBP7, with statistically significant cf-NRIs but non-significant IDIs. Post-surgery TIMP-2 and IGFBP predicted 30-day mortality, with C-statistics of 0.74 and 0.80. In conclusion, in elective cardiac surgery patients, pre- and peri-operative clinical variables were highly discriminating about which patients required RRT after surgery. Nonetheless, in elective cardiac surgery patients, urinary TIMP-2 and IGFBP7 improved prediction of RRT and 30-day mortality post-surgery.

Phosphate binders such as sevelamer are widely used in patients with chronic kidney disease to lower serum phosphate levels. We present a case of a 67-year-old woman with lower gastrointestinal bleeding after 9 days of using sevelamer carbonate (Renvela®). Sigmoidoscopy revealed multiple deep ulcers (diameter 10–15 mm) and mucosal oedema. Histologic examination showed deposition of sevelamer crystals in these rectal ulcers. We hypothesized that the lower gastrointestinal bleeding was caused by deposition of sevelamer crystals. After cessation of sevelamer, gastrointestinal bleeding stopped. Deposition of sevelamer crystals in the gastrointestinal tract is a rare complication of sevelamer therapy. There are only 17 other recorded cases of gastrointestinal deposition of sevelamer crystals. This adverse effect should be considered in all patients taking sevelamer who present with gastrointestinal symptoms, such as gastrointestinal bleeding and abdominal pain. When sevelamer is discontinued, symptoms and mucosal damage appear to revert.

Kidney international / Reports 5(8), 1327-1332 (2020). doi:10.1016/j.ekir.2020.05.030, Published by Elsevier, Amsterdam

Current models for flu-like epidemics insufficiently explain multi-cycle seasonality. Meteorological factors alone, including associated behavior, do not predict seasonality, given substantial climate differences between countries that are subject to flu-like epidemics or COVID-19. Pollen is documented to be antiviral, anti-influenza and allergenic, plays a role in immuno-activation, and seems to create a bio-aerosol lowering the reproduction number of flu-like viruses. Therefore, we hypothesize that pollen may explain the seasonality of flu-like epidemics including COVID-19.We tested the Pollen-Flu Seasonality Theory for 2016–2020 flu-like seasons, including COVID-19, in The Netherlands with its 17 million inhabitants. We combined changes in flu-like incidence per 100K/Dutch citizens (code: ILI) with weekly pollen counts and meteorological data. Finally, a discrete, predictive model is tested using pollen and meteorological threshold values displaying inhibitory effects on flu-like incidence.We found a highly significant inverse association of r(224) = –.38 between pollen and changes in flu-like incidence corrected for incubation period, confirming our expectations for the 2019/2020 COVID-19 season. The associations become stronger when taking into account incubation time, which satisfies the temporality criteria. We found that our predictive model has the highest inverse correlation with changes in flu-like incidence of r(222) = –.48 (p < .001) when thresholds of 610 total pollen grains/m3 per week, 120 allergenic pollen grains/m3 per week, and a solar radiation of 510 J/cm2 are passed. The passing of at least the pollen thresholds, preludes the beginning and end of flu-like seasons. Solar radiation is a supportive factor, temperature makes no difference, and relative humidity associates even with flu-like incidence increases.We conclude that pollen is a predictor for the inverse seasonality of flu-like epidemics including COVID-19, and solar radiation is a co-inhibitor. The observed seasonality of COVID-19 during Spring, suggests that COVID-19 may revive in The Netherlands after week 33, the start being preceded by the relative absence of pollen, and follows standard pollen-flu seasonality patterns.

Background and Aims Both hypo- and hyperkalemia can potentially induce fatal cardiac arrhythmias in the general population. However, little is known about the effect of potassium as a modifiable risk factor in hemodialysis (HD) patients. Therefore, we investigated the relation between serum potassium level and all-cause mortality in incident HD patients and whether there is an optimum serum potassium level to pursue. Method All incident HD patients (>18 y) from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), a prospective multi-center cohort study, were included. These patients were followed from the start of their first dialysis treatment until death, transplantation or a maximum of 2 years. Serum potassium levels were obtained at fixed 6-month time intervals and divided into six categories: ≤ 4.0, > 4.0 - ≤ 4.5, > 4.5 - ≤ 5.0, > 5.0 - ≤ 5.5 (reference), > 5.5 - ≤ 6.0 and > 6.0 mmol/L. Using a Cox proportional-hazards model with serum potassium category as a time-dependent variable, hazard ratios (HR) for all-cause mortality were calculated, adjusted for baseline age, sex, current smoking, diabetes and residual kidney function. Results In total, 1278 HD patients were included. At baseline, mean (±SD) age was 64 (±14) years, 60% were men, 23% were current smokers, 21% had diabetes and the median (interquartile range) residual kidney function was 3.0 (1.5-4.8) ml/min/1.73m2. Mean (±SD) serum potassium level was 4.8 (±0.8) mmol/L. The prevalence of the six potassium categories was: 10%, 19%, 26%, 22%, 15% and 8%, respectively. A total of 298 (23%) deaths was observed during 2 years of follow-up. After multivariable adjustment the HR (95% CI) for any death according to the six potassium categories were: 2.5 (1.5-4.3), 1.9 (1.2-3.0), 1.6 (1.0-2.5), 1 (reference), 1.3 (0.8-2.2) and 1.7 (1.0-3.0). Conclusion We found a U-shaped relation between serum potassium and all-cause mortality in incident hemodialysis patients. Especially, low serum potassium was a 2.5-fold stronger risk factor for all-cause mortality compared to normal serum potassium. Our results indicate an optimum serum potassium level between 5.0 - 5.5 mmol/L, emphasizing that potassium lowering therapy should be used with caution in hemodialysis patients.

Rationale & Objective: Chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2), is a risk factor for cardiovascular morbidity and mortality. Little is known about low birth weight and risk for CKD in middle-aged adults in the general population. We estimated the causal association between birth weight and eGFR in a Dutch cohort of middle-aged men and women.Study Design: Retrospective cohort study.Setting & Participants: 6,671 participants in the Netherlands Epidemiology of Obesity (NEO) Study. Replication study using data for 133,814 participants studied by the CKDGen consortium.Exposure: Birth weight was self-reported and also based on an instrumental variable, 59 birth weight-associated genetic variants, derived from an independent data source.Outcome: eGFR at the age of 45 to 65 years.Analytical Approach: We assessed the association between self-reported birth weight and eGFR in the NEO Study using multivariable linear regression, adjusted for age, sex, education, smoking, and alcohol use. The effect of the instrument on eGFR was estimated using separate 2-sample Mendelian randomization analyses: one using individual data from the NEO cohort and one using summary data from the CKDGen consortium.Results: At baseline, mean eGFR was 86 +/- 12.4 (SD) mL/min/1.73 m(2). After multivariable adjustment, self-reported birth weight was not associated with kidney function in middle age. Two-sample Mendelian randomization analysis showed that in the NEO cohort, for each 500-g lower birth weight defined using genetic variants, there was a 3.7 (95% CI, 0.5-6.9)-mL/ min/1.73 m(2) lower eGFR at the age of 45 to 65 years. However, using CKDGen summary-level data, there was a smaller nonsignificant relationship between birth weight and eGFR.Limitations: Birth weight was self-reported.Conclusions: Lower birth weight defined using genetic variants was associated with lower eGFRs in Dutch middle-aged adults. However, this finding was not replicated within the CKDGen consortium.

Previous studies showed that statins reduce the progression of kidney function decline and proteinuria, but whether specific types of statins are more beneficial than others remains unclear. We performed a network meta-analysis of randomized controlled trials (RCT) to investigate which statin most effectively reduces kidney function decline and proteinuria. We searched MEDLINE, Embase, Web of Science, and the Cochrane database until July 13, 2018, and included 43 RCTs (>110,000 patients). We performed a pairwise random-effects meta-analysis and a network meta-analysis according to a frequentist approach. We assessed network inconsistency, publication bias, and estimated for each statin the probability of being the best treatment. Considerable heterogeneity was present among the included studies. In pairwise meta-analyses, 1-year use of statins versus control reduced kidney function decline by 0.61 (95%-CI: 0.27; 0.95) mL/min/1.73 m2 and proteinuria with a standardized mean difference of −0.58 (95%-CI:−0.88; −0.29). The network meta-analysis for the separate endpoints showed broad confidence intervals due to the small number available RCTs for each individual comparison. In conclusion, 1-year statin use versus control attenuated the progression of kidney function decline and proteinuria. Due to the imprecision of individual comparisons, results were inconclusive as to which statin performs best with regard to renal outcome.

Background and objectives Little is known about the functional course after initiating dialysis in elderly patients with ESKD. The aim of this study was to assess the association of the initiation of dialysis in an elderly population with functional status and caregiver burden. Design, setting, participants & measurements This study included participants aged ≥65 years with ESKD who were enrolled in the Geriatric Assessment in Older Patients Starting Dialysis study. All underwent a geriatric assessment and a frailty screening (Fried Frailty Index and Groningen Frailty Indicator) at dialysis initiation. Functional status (activities of daily life and instrumental activities of daily life) and caregiver burden were assessed at baseline and after 6 months. Decline was defined as loss of one or more domains in functional status, stable as no difference between baseline and follow-up, and improvement as gain of one or more domains in functional status. Logistic regression was performed to assess the association between the combined outcome functional decline/death and potential risk factors. Results Of the 196 included participants functional data were available for 187 participants. Mean age was 75±7 years and 33% were women. At the start of dialysis, 79% were care dependent in functional status. After 6 months, 40% experienced a decline in functional status, 34% remained stable, 18% improved, and 8% died. The prevalence of high caregiver burden increased from 23%–38% (P=0.004). In the multivariable analysis age (odds ratio, 1.05; 95% confidence interval, 1.00 to 1.10 per year older at baseline) and a high Groningen Frailty Indicator compared with low score (odds ratio, 1.97; 95% confidence interval, 1.05 to 3.68) were associated with functional decline/death. Conclusions In patients aged ≥65 years, functional decline within the first 6 months after initiating dialysis is highly prevalent. The risk is higher in older and frail patients. Loss in functional status was mainly driven by decline in instrumental activities of daily life. Moreover, initiation of dialysis is accompanied by an increase in caregiver burden.

Background and Objectives: A geriatric assessment (GA) is a structural method for identifying frail patients. The relation of GA findings and risk of death in end-stage kidney disease (ESKD) is not known. The objective of the GA in OLder patients starting Dialysis Study was to assess the association of GA at dialysis initiation with early mortality and hospitalization. Design, Setting, Participants, and Measurements: Patients ≥65 years old were included just prior to dialysis initiation. All participants underwent a GA, including assessment of (instrumental) activities of daily living (ADL), mobility, cognition, mood, nutrition, and comorbidity. In addition, a frailty screening (Fried Frailty Index, [FFI]) was applied. Outcome measures were 6- and 12-month mortality, and 6-month hospitalization. Associations with mortality were assessed with cox-regression adjusting for age, sex, comorbidity burden, smoking, residual kidney function and dialysis modality. Associations with hospitalization were assessed with logistic regression, adjusting for relevant confounders. Results: In all, 192 patients were included, mean age 75 ± 7 years, of whom 48% had ≥3 geriatric impairments and were considered frail. The FFI screening resulted in 46% frail patients. Mortality rate was 8 and 15% at 6- and 12-months after enrolment, and transplantation rate was 2 and 4% respectively. Twelve-month mortality risk was higher in patients with ≥3 impairments (hazard ratio [HR] 2.97 [95% CI 1.19–7.45]) compared to less impaired patients. FFI frail patients had a higher risk of 12-month mortality (HR 7.22 [95% CI 2.47–21.13]) and hospitalization (OR 1.93 [95% CI 1.00–3.72]) compared to fit patients. Malnutrition was associated with 12-month mortality, while impaired ADL and depressive symptoms were associated with 12-month mortality and hospitalization. Conclusions: Frailty as assessed by a GA is related to mortality in elderly patients with ESKD. Individual components of the GA are related to both mortality and hospitalization. As the GA allows for distinguishing between frail and fit patients initiating dialysis, it is potentially of added value in the decision-making process concerning dialysis initiation.

Introduction: Impaired kidney function is a robust risk factor for cardiovascular mortality. Age-related annual kidney function decline of 1.0 ml/min per 1.73 m2 after age 40 years is doubled in post−myocardial infarction (MI) patients. Methods: We investigated the impact of the number of cardiovascular risk factors (including unhealthy lifestyle) on annual kidney function decline, in 2426 post-MI patients (60−80 years) of the prospective Alpha Omega Cohort study. Glomerular filtration rate was estimated by serum cystatin C (eGFRcysC) and combined creatinine−cystatin C (eGFRcr-cysC), using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations from 2012. Data were analyzed by multivariable linear and logistic regression. Results: At baseline, mean (SD) eGFRcysC and eGFRcr-cysC were 81.5 (19.6) and 78.5 (18.7) ml/min per 1.73 m2, respectively. Of all patients, 79% were men, 19% had diabetes, 56% had high blood pressure (≥140/90 mm Hg), 16% were current smokers, 56% had high serum low-density lipoprotein (LDL of ≥2.5 mmol/l), and 23% were obese (body mass index of ≥30.0 kg/m2). After multivariable adjustment, the additional annual eGFRcysC decline (95% confidence interval) was as follows: in patients with versus without diabetes, −0.90 (−1.23 to −0.57) ml/min per 1.73 m2; in patients with high versus normal blood pressure, −0.50 (−0.76 to −0.24) ml/min per 1.73 m2; in obese versus nonobese patients, −0.31 (−0.61 to 0.01) ml/min per 1.73 m2; and in current smokers versus nonsmokers, −0.19 (−0.54 to 0.16) ml/min per 1.73 m2. High LDL was not associated with accelerated eGFRcysC decline. Similar results were obtained with eGFRcr-cysC. Conclusion: In older, stable post-MI patients without cardiovascular risk factors, the annual kidney function decline was −0.90 (−1.16 to −0.65) ml/min per 1.73 m2. In contrast, in post-MI patients with ≥3 cardiovascular risk factors, the annual kidney function decline was 2.5-fold faster, at −2.37 (−2.85 to −1.89) ml/min per 1.73 m2. Keywords: cardiovascular risk factors, kidney function decline, lifestyle

Lower body mass index (BMI) has consistently been associated with mortality in elderly in the general and chronic disease populations. Remarkably, in older incident dialysis patients no association of BMI with mortality was found. We performed an in-depth analysis and explored possible time-stratified effects of BMI. 908 incident dialysis patients aged ≥65 years of the NECOSAD study were included, and divided into tertiles by baseline BMI (2). Because the hazards changed significantly during follow-up, the effect of BMI was modeled for the short-term (P = 0.007), and lower longer-term mortality risk (adjusted-HR 0.81 [0.63–1.04] P = 0.1). Patients with lower BMI who died during the first year had significantly more comorbidity, and worse self-reported physical functioning compared with those who survived the first year. Thus, lower BMI is associated with increased 1-year mortality, but conditional on surviving the first year, lower BMI yielded a similar or lower mortality risk compared with the reference. Those patients with lower BMI, who had limited comorbidity and better physical functioning, had better survival.

Background Obesity increases risk of hypertension and diabetes, the leading causes of end-stage renal disease. The effect of obesity on kidney function decline in stable post-myocardial infarction patients is poorly documented. This relation was investigated in a large cohort of older post-myocardial infarction patients. Design Data were analysed from 2410 post-myocardial infarction patients in the Alpha Omega Trial, aged 60–80 years receiving optimal pharmacotherapy treatment (79% men, 18% diabetes). Methods Cystatin C based estimated glomerular filtration rate (eGFRcysC) was calculated at baseline and after 41 months, using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Obesity was defined as body mass index ≥ 30 kg/m2 and high waist circumference as ≥102 and ≥88 cm for men and women. The relation between body mass index, waist circumference and annual eGFRcysC decline was evaluated by linear regression. Results At baseline, mean (standard deviation) eGFRcysC was 81.5 (19.6) ml/min/1.73 m2, 23% of all patients were obese. After multivariable adjustment, the annual mean (95% confidence interval) eGFRcysC decline in men and women was –1.45 (–1.59 to –1.31) and –0.92 (–1.20 to –0.63) ml/min/1.73 m2, respectively ( p = 0.001). Obese versus non-obese patients and patients with high versus normal waist circumference experienced greater annual eGFRcysC decline. Men and women showed an additional annual eGFRcysC decline of –0.35 (–0.56 to –0.14) and –0.21 (–0.55 to 0.14) ml/min/1.73 m2 per 5 kg/m2 body mass index increment ( p for interaction 0.3). Conclusions High compared to normal body mass index or waist circumference were associated with more rapid kidney function decline in older stable post-myocardial infarction patients receiving optimal drug therapy.

Fibroblast growth factor 23 (FGF23) is an independent risk factor for cardiovascular mortality in chronic kidney disease. Omega-3 (n-3) fatty acid consumption has been inversely associated with FGF23 levels and with cardiovascular risk. We examined the effect of marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and plant-derived alpha-linolenic acid (ALA) on plasma FGF23 levels in post-myocardial infarction patients with chronic kidney disease. In the randomized double-blind Alpha Omega Trial, 4837 patients with a history of myocardial infarction aged 60–80 years (81% men) were randomized to one of four trial margarines supplemented with a targeted additional intake of 400 mg/day EPA and DHA, 2 g/day ALA, EPA-DHA plus ALA, or placebo for 41 months. In a subcohort of 336 patients with an eGFR < 60 mL/min/1.73 m2 (creatinine-cystatin C-based CKD-EPI formula), plasma C-terminal FGF23 was measured by ELISA at baseline and end of follow-up. We used analysis of covariance to examine treatment effects on FGF23 levels adjusted for baseline FGF23. Patients consumed 19.8 g margarine/day on average, providing an additional amount of 236 mg/day EPA with 158 mg/day DHA, 1.99 g/day ALA or both, in the active intervention groups. Over 79% of patients were treated with antihypertensive and antithrombotic medication and statins. At baseline, plasma FGF23 was 150 (128 to 172) RU/mL (mean (95% CI)). After 41 months, overall FGF23 levels had increased significantly (p < 0.0001) to 212 (183 to 241) RU/mL. Relative to the placebo, the treatment effect of EPA-DHA was indifferent, with a mean change in FGF23 (95% CI) of −17 (−97, 62) RU/mL (p = 0.7). Results were similar for ALA (36 (−42, 115) RU/mL) and combined EPA-DHA and ALA (34 (−44, 113) RU/mL). Multivariable adjustment, pooled analyses, and subgroup analyses yielded similar non-significant results. Long-term supplementation with modest quantities of EPA-DHA or ALA does not reduce plasma FGF23 levels when added to cardiovascular medication in post-myocardial patients with chronic kidney disease. Keywords: n-3 polyunsaturated fatty acids; fibroblast growth factor 23; myocardial infarction; chronic kidney disease; cardiovascular

Globally the number of patients on renal replacement therapy (RRT) is rising. Dyslipidemia is a potential modifiable cardiovascular risk factor, but its effect on risk of RRT or death in pre-dialysis patients is unclear. The aim of this study was to assess the association between dyslipidemia and risk of RRT or death among patients with CKD stage 4–5 receiving specialized pre-dialysis care, an often under represented group in clinical trials. Of the 502 incident pre-dialysis patients (>18 y) in the Dutch PREPARE-2 study, lipid levels were available in 284 patients and imputed for the other patients. During follow up 376 (75%) patients started RRT and 47 (9%) patients died. Dyslipidemia was defined as total cholesterol ≥5.00 mmol/L, LDL cholesterol ≥2.50 mmol/L, HDL cholesterol

A 74-year-old hemodialysis patient with a history of an atrial septum defect closure, coronary bypass surgery, and a St. Jude aortic prosthetic valve was diagnosed with pneumonia and volume overload. Blood cultures were positive for Listeria monocytogenes, and amoxicillin was given for 2 weeks. Immediately after discontinuation of amoxicillin, fever relapsed. Transthoracic and transesophageal echocardiography showed no sign of endocarditis. Given the fever relapse and 3 positive minor Duke criteria, an 18F-FDG PET-CT scan (18F-fluorodeoxyglucose-positron emission tomography-computed tomography) scan was performed. This scan showed activity at the aortic root, proximal ascending aorta, and inferior wall of the heart, making Listeria monocytogenes endocarditis a likely explanation. Amoxicillin was given for 6 weeks with good clinical result. Diagnosing a life-threatening Listeria monocytogenes endocarditis can be challenging and an 18F-FDG PET-CT scan can be helpful.

Chronic kidney disease (CKD) is highly prevalent among older post-myocardial infarction (MI) patients. It is not known whether CKD is an independent risk factor for mortality in older post-MI patients with optimal cardiovascular drug-treatment. Therefore, we studied the relation between kidney function and all-cause and specific mortality among older post-MI patients, without severe heart failure, who are treated with state-of-the-art pharmacotherapy. From 2002–2006, 4,561 Dutch post-MI patients were enrolled and followed until death or January 2012. We estimated Glomerular Filtration Rate (eGFR) with cystatin C (cysC) and creatinine (cr) using the CKD-EPI equations and analyzed the relation with any and major causes of death using Cox models and restricted cubic splines. Mean (SD) for age was 69 years (5.6), 79% were men, 17% smoked, 21% had diabetes, 90% used antihypertensive drugs, 98% used antithrombotic drugs and 85% used statins. Patients were divided into four categories of baseline eGFRcysC: ≥90 (33%; reference), 60–89 (47%), 30–59 (18%), and

Background The aim was to investigate whether mild kidney dysfunction and low-grade inflammation in post-myocardial infarction patients are independently associated with markers of mental well-being (i.e. depressive and apathy symptoms, and dispositional optimism). Methods In post-myocardial infarction patients, kidney function was assessed by estimated glomerular filtration rate (eGFR) calculated from the combined CKD-EPI formula based on serum levels of both creatinine and cystatine C. Systemic inflammation was assessed using high sensitivity C-reactive protein (hs-CRP) levels. The 15-item Geriatric Depression Scale (GDS-15), the 3-item apathy subscale and the 4-item optimism questionnaire (4Q) were used to measure mental well-being and were analyzed using linear multivariable regression analysis. Results Of the 2355 patients, mean age was 72.3 (range 63–84) years and 80.1% were men. After multivariable adjustment, a poorer kidney function was associated with more depressive symptoms (β = -0.084, p < 0.001), more apathy symptoms (β = -0.101, p < 0.001), and less dispositional optimism (β = 0.072, p = 0.002). Moreover, higher levels of hs-CRP were associated with more depressive symptoms (β = 0.051, p = 0.013), more apathy symptoms (β = 0.083, p < 0.001) and less dispositional optimism (β = -0.047 p = 0.024). Apathy showed the strongest independent relation with both low eGFR and high hs-CRP. Conclusions In post-myocardial infarction patients, impaired kidney function and systemic inflammation showed a stronger association with apathy than with depressive symptoms and dispositional optimism.

BACKGROUND: Obesity is associated with increased mortality and accelerated decline in kidney function in the general population. Little is known about the effect of obesity in younger and older pre-dialysis patients. The aim of this study was to assess the extent to which obesity is a risk factor for death or progression to dialysis in younger and older patients on specialized pre-dialysis care.METHOD: In a multicenter Dutch cohort study, 492 incident pre-dialysis patients (>18y) were included between 2004-2011 and followed until start of dialysis, death or October 2016. We grouped patients into four categories of baseline body mass index (BMI): RESULTS: The study population comprised 212 patients younger than 65 years and 280 patients 65 years and older; crude cumulative risk of dialysis and mortality at the end of follow-up were 66% and 4% for patients CONCLUSION: We found that obesity in younger pre-dialysis patients and being underweight in older pre-dialysis patients are risk factors for starting dialysis and for death, compared with those with a normal BMI.

Item does not contain fulltext Originally described as a proliferative glomerulonephritis, C1q nephropathy is nowadays mostly recognized as a variant of focal segmental glomerulosclerosis or minimal change disease. We describe a 30-year-old male patient with nephrotic range proteinuria. Kidney biopsy demonstrated a membranous nephropathy with predominant staining for C1q. Under conservative therapy the outcome was favorable. We suggest that this case represents another variant of C1q nephropathy, thus broadening the spectrum of the disease. 01 juni 2012

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A 43-year-old haemodialysis patient was admitted to hospital because of paroxysmal pain in the upper abdominal region radiating to the back. Laboratory tests showed severe hyperparathyroidism [intact parathyroid hormone (iPTH) 69 pmol/L; reference range: 1.3-6.8 pmol/L], hypercalcaemia (2.79 mmol/L), hyperphosphataemia (1.6 mmol/L) and elevated serum total alkaline phosphatase (200 U/L). After developing a disturbed sensation and paraesthesia in both feet, epidural compression of the spinal cord was suspected. Magnetic resonance imaging showed a tumour that severely compressed the myelum of the thoracic spine. Histological investigation revealed a brown tumour or osteoclastoma, an erosive bony lesion caused by increased osteoclastic activity and peritrabecular fibrosis. A brown tumour is a benign tumour that is a rare complication of severe renal hyperparathyroidism. The brown tumour developed despite a 1-year treatment of the patient with cinacalcet, which, however, did not result in a major decrease in serum iPTH concentration (from 110 to 69 pmol/L: 37% reduction). Urgent decompressive neurosurgery and subtotal parathyroidectomy resulted in a complete recovery.

Contains fulltext : 69969.pdf (Publisher’s version ) (Closed access) The prevalence of cardiovascular risk factors in renal transplant candidates is high. A better understanding of the relation between these risk factors and cardiovascular morbidity and mortality is mandatory to improve transplantation outcome. In this retrospective cohort study 2187 adult patients who received a first kidney transplant between 1984 and 1997 were included. We analyzed the incidence of post-transplant cardiovascular events and tried to identify independent pretransplant risk factors for post-transplant cardiovascular events and all-cause mortality. The cumulative incidence of post-transplant cardiovascular events was 40%. The incidence was highest in the first 3 months after transplantation. Independent pretransplant risk factors for a post-transplant cardiovascular event were diabetic nephropathy [Hazard ratio (HR) 3.02; 95% CI 2.85-3.98], claudication [HR 2.17 (1.42-3.31)], cardiac event [HR 1.76 (1.32-2.33)], cerebrovascular accident HR 1.53 (1.03-2.28), time-on-dialysis [HR 1.06 (1.02-1.11)], recipient age [HR 1.04 (1.04-1.05)], and body mass index [HR 1.03 (1.00-1.05)]. Diabetic nephropathy and cardiovascular disease were also important predictors for all-cause mortality. Diabetic nephropathy and cardiovascular disease were the most important predictors for cardiovascular events and all-cause mortality after renal transplantation. Early treatment of cardiovascular risk factors and pretransplant cardiovascular evaluation might improve transplantation outcome.

Background. The prevalence of obesity is increasing globally and is associated with chronic kidney disease and premature mortality. However, the impact of recipient obesity on kidney transplant outcomes remains unclear. This study aimed to investigate the association between recipient obesity and mortality, death-censored graft loss and delayed graft function (DGF) following kidney transplantation. Methods. A systematic review and meta-analysis was conducted using Medline, Embase and the Cochrane Library. Observationalstudiesorrandomizedcontrolledtrialsinvestigating the association between recipient obesityat transplantation and mortality, death-censored graft loss and DGF were included. Obesity was defined as a body mass index (BMI) of ≥30 kg/m 2 . Obese recipients were compared with those with a normal BMI (18.5–24.9 kg/m 2 ). Pooled estimates of hazard ratios (HRs) for patient mortality or death-censored graft loss and odds ratios (ORs) for DGF were calculated. Results.Seventeen studiesincluding138 081patients wereanalysed. After adjustment, there was no significant difference in mortality risk in obese recipients [HR = 1.24, 95% confidence interval (CI) = 0.90–1.70, studies = 5, n= 83 416]. However, obesity was associated with an increased risk of death-censored graft loss (HR = 1.06, 95% CI = 1.01–1.12, studies = 5, n =8 3 416) and an increased likelihood of DGF (OR = 1.68, 95% CI = 1.39–2.03, studies = 4, n = 28 847). Conclusions. Despite having a much higher likelihood of DGF, obese transplant recipients have onlya slightly increased riskof graft loss and experience similar survival to recipients with normal BMI.