Association between reduced kidney function and incident hypoglycaemia in people with diabetes: The Stockholm Creatinine Measurements (SCREAM) project.

AIM: To evaluate possible associations between estimated glomerular filtration rate (eGFR) and hypoglycaemia in adults with diabetes. METHODS: We conducted an observational study in adults with diabetes from the Stockholm Creatinine Measurement (SCREAM) project, a Swedish healthcare utilization cohort during 2007 to 2011. We evaluated diagnoses and outpatient glucose tests for incidence rate ratios (IRRs) of hypoglycaemia (overall and by severity) in outpatient care by eGFR strata using zero-inflated negative binomial regression. We identified clinical predictors through ordinal logistic regression and assessed 7-day and 30-day mortality from hypoglycaemia in relation to eGFR with Cox proportional hazard models. RESULTS: We identified 29 434 people with diabetes (13% with type 1 diabetes). Their mean age was 66 years, 43% were women and the median eGFR was 80 mL/min/1.73 m2 . During 2 years of follow-up, 1812 patients (6.2%) had hypoglycaemia registered at least once. The risk of hypoglycaemia increased linearly with lower eGFR, with an IRR of 1.2 (95% confidence interval [CI] 1.0-1.4) for eGFR 60-89 mL/min/1.73 m2 and 5.8 (95% CI 3.8-9.0) for eGFR <15 mL/min/1.73 m2 compared to eGFR 90 to 104 mL/min/1.73 m2 . This trend was observed for both mild and severe hypoglycaemia. Both 7-day and 30-day post-hypoglycaemia mortality increased with lower eGFR, peaking in those with eGFR <15 mL/min/1.73 m2 (hazard ratio 21.2, 95% CI 5.1-87.9) as compared to those with eGFR 90 to 104 mL/min/1.73 m2 . Lower eGFR categories, type 1 diabetes, previous hypoglycaemia, liver disease, presence of diabetic complications and use of insulin and sulphonylureas increased the odds of hypoglycaemia. CONCLUSION: In this large, observational study, low eGFR was strongly associated with the occurrence, severity and fatality of hypoglycaemia in people with diabetes.

Effects of acute fructose loading on levels of serum uric acid-a pilot study.

BACKGROUND: Fructose intake may lead to hyperuricaemia, which is associated with increased risk and progression of kidney disease. We aimed to explore the acute effects of fructose loading from different sources, with and without a pizza, on levels of serum uric acid in patients with chronic kidney disease (CKD), type 2 diabetes (T2D) without CKD, and in healthy subjects (HS). METHODS: The study included six HS, and three CKD stage 4-5 and seven T2D patients. Drinks consumed were blueberry drink (17.5 g fructose), Coca-Cola (18 g fructose) and fructose drink (35 g fructose). The drinks were also combined with pizza, in total six interventions. Serum samples were collected fasting and 30, 60, 90 and 120 minutes after intake and also 240 minutes after drink + pizza, and analysed for fructose, uric acid and triglycerides. Postprandial responses were explored using repeated-measure ANOVA. RESULTS: Baseline serum uric acid levels were increased in CKD (P = 0.037). There were significant differences in serum fructose and serum uric levels over time between drinks and drinks + pizza for all groups (P < 0.001 and P < 0.05, respectively). The highest peak in serum fructose followed the fructose drink interventions and the lowest the blueberry drink. The fructose drink interventions gave the highest responses in serum uric acid and the lowest responses followed the blueberry drink. Triglycerides increased following pizza interventions (P < 0.001). CONCLUSIONS: Intake of fructose increases serum uric acid. The fructose intake via a blueberry drink induced lowest increase and thus may be protective.

Albuminuria changes are associated with subsequent risk of end-stage renal disease and mortality.

Current guidelines for chronic kidney disease (CKD) recommend using albuminuria as well as estimated glomerular filtration rate (eGFR) to stage CKD. However, CKD progression is solely defined by change in eGFR with little regard to the risk implications of change in albuminuria. This is an observational study from the Stockholm CREAtinine Measurements (SCREAM) project, a health care utilization cohort from Stockholm, Sweden, with laboratory measures from 2006-2011 and follow-up through December 2012. Included were 31,732 individuals with two or more ambulatory urine albumin to creatinine ratio (ACR) tests. We assessed the association between change in ACR during a baseline period of 1, 2, or 3 years and end-stage renal disease (ESRD) or death. Using a 2-year baseline period, there were 378 ESRD events and 1712 deaths during a median of 3 years of follow-up. Compared to stable ACR, a 4-fold increase in ACR was associated with a 3.08-times (95% confidence interval 2.59 to 3.67) higher risk of ESRD while a 4-fold decrease in ACR was associated with a 0.34-times (0.26 to 0.45) lower risk of ESRD. Similar associations were found in people with and without diabetes mellitus, with and without hypertension, and also when adjusted for the change in eGFR during the same period. The association between change in ACR and mortality was weaker: ACR increase was associated with mortality, but the relationship was largely flat for ACR decline. Results were consistent for 1-, 2-, and 3-year ACR changes. Thus, changes in albuminuria are strongly and consistently associated with the risk of ESRD and death.

Initiation of erythropoiesis-stimulating agents and outcomes: a nationwide observational cohort study in anaemic chronic kidney disease patients.

BACKGROUND: In 2012, new clinical guidelines were introduced for use of erythropoiesis-stimulating agents (ESA) in chronic kidney disease (CKD) patients, recommending lower haemoglobin (Hb) target levels and thresholds for ESA initiation. These changes resulted in lower blood levels in these patients. However, there is limited evidence on just when ESA should be initiated and the safety of a low Hb initiation policy. METHODS: In this observational inception cohort study, Swedish, nephology-referred, ESA-naïve CKD patients (n = 6348) were enrolled when their Hb dropped below 12.0 g/L, and they were followed for mortality and cardiovascular events. Four different ESA treatments were evaluated applying dynamic marginal structural models: (i) begin ESA immediately, (ii) begin ESA when Hb <11.0 g/dL, (iii) begin ESA when Hb <10.0 g/dL and (iv) never begin ESA in comparison with 'current practice' [the observed (factual) survival of the entire study cohort]. The adjusted 3-year survival following ESA begun over a range of Hb (from <9.0 to 12.0 g/dL) was evaluated, after adjustment for covariates at baseline and during follow-up. RESULTS: Overall, 36% were treated with ESA. Mortality during follow-up was 33.4% of the ESA-treated and 27.9% of the non-treated subjects. The adjusted 3-year survival associated with ESA initiation improved for subjects with initial Hb <9.0 to 11 g/dL and then decreased again for those with Hb above 11.5 g/dL. Initiating ESA at Hb <11.0 g/dL and <10.0 g/dL was associated with improved survival compared with 'current practice' [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.79-0.89 and 0.90; 95% CI 0.86-0.94, respectively] and did not increase the risk of a cardiovascular event (HR 0.93; 95% CI 0.87-1.00). CONCLUSION: In non-dialysis patients with CKD, ESA initiation at Hb < 10.0-11.0 g/dL is associated with improved survival in patients otherwise treated according to guidelines.

Trends in haemoglobin, erythropoietin-stimulating agents and iron use in Swedish chronic kidney disease patients between 2008 and 2013.

BACKGROUND: The guidelines for anaemia management in chronic kidney disease (CKD) patients have changed substantially during the past 10 years. We here evaluate whether these changes are followed by subsequent modifications in physicians' anaemia management in Sweden. METHODS: We included patients incident to the Swedish Renal Registry for CKD non-dialysis (CKD-ND, referred patients with an estimated glomerular filtration rate <45 mL/min/1.73 m(2)) and haemodialysis (HD) between 2008 and 2013. Time trends in anaemia management were investigated in relation to prescribed medication, laboratory measures and other relevant clinical characteristics. Linear and binominal regression models were used to describe trends across three predefined time periods (2008-09, 2010-11 and 2012-13). RESULTS: Erythropoiesis-stimulating agents (ESAs) use decreased over time among both CKD-ND and HD patients [risk ratio (RR) 2012-13 compared with 2008-09 for CKD-ND 0.88, 95% confidence interval (CI) 0.81-0.96; RR for HD 0.95, 95% CI 0.93-0.97]. Mean ESA dose decreased significantly among HD patients (7% in 2010-11 compared with 2008-09 and another 3% during 2012-13). Over the time periods studied, ESA doses increased slightly in the CKD-ND population. Mean haemoglobin (Hb) levels decreased in CKD-ND patients, among both ESA users and non-users, whereas it decreased to a lesser degree, albeit significantly, among HD ESA users. The risk of having an Hb >120 g/L decreased, especially between 2008-09 and 2010-11. Iron use increased over time, mainly in the HD population, but also among CKD-ND ESA non-users. CONCLUSIONS: Changes in guidelines have influenced the clinical anaemia practice of Swedish nephrology care, resulting in lower ESA use and lower Hb levels.

Dialysis modality and nutritional status are associated with variability of inflammatory markers.

BACKGROUND: Inflammation is a common feature in dialysis patients and is associated with cardiovascular complications and poor outcome. Measuring the variability of inflammatory markers may help in understanding underlying factors triggering inflammation. Whether the inflammatory pattern in hemodialysis (HD) and peritoneal dialysis (PD) patients differs has scarcely been studied. Here we explored factors associated with the magnitude and variability of inflammation markers in HD and PD patients. METHODS: In two 3-month, prospective cohort studies comprising 228 prevalent HD and 80 prevalent PD patients, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRP) were measured in blood samples drawn each month and every week, respectively. Information on comorbidity, protein-energy wasting (PEW) and medications was gathered at baseline, and information on symptoms potentially related to inflammation was gathered weekly. A mixed-effect model was used for multivariate analysis of factors linked to CRP and IL-6 variation. RESULTS: IL-6 and CRP levels were higher and showed higher variability in HD versus PD patients [median IL-6 8.3 (interquartile range, IQR, 5.3-14.5) versus 6.7 (IQR 4.2-10.0) pg/mL, P < 0.001 and median CRP 6.1 (IQR 2.5-14.0) versus 5.4 (IQR 1.6-9.0) mg/L, P < 0.001). PEW predicted increased inflammation variability after correcting for age, sex, dialysis vintage, modality and comorbidity. Increased comorbidity predicted IL-6, but not CRP, variability. CONCLUSIONS: Circulating concentrations as well as variability of IL-6 and CRP levels were higher in HD as compared with PD patients. In HD and PD patients, short-term variability of IL-6 and CRP levels associated strongly with PEW, while comorbidity was related to IL-6 but not to CRP variability.

Prevalence and recognition of chronic kidney disease in Stockholm healthcare.

BACKGROUND: Chronic kidney disease (CKD) is common, but the frequency of albuminuria testing and referral to nephrology care has been difficult to measure. We here characterize CKD prevalence and recognition in a complete healthcare utilization cohort of the Stockholm region, in Sweden. METHODS: We included all adult individuals (n = 1 128 058) with at least one outpatient measurement of IDMS-calibrated serum creatinine during 2006-11. Estimated glomerular filtration rate (eGFR) was calculated via the CKD-EPI equation and CKD was solely defined as eGFR <60 mL/min/1.73 m2. We also assessed the performance of diagnostic testing (albuminuria), nephrology consultations, and utilization of ICD-10 diagnoses. RESULTS: A total of 68 894 individuals had CKD, with a crude CKD prevalence of 6.11% [95% confidence interval (CI): 6.07-6.16%] and a prevalence standardized to the European population of 5.38% (5.33-5.42%). CKD was more prevalent among the elderly (28% prevalence >75 years old), women (6.85 versus 5.24% in men), and individuals with diabetes (17%), hypertension (17%) or cardiovascular disease (31%). The frequency of albuminuria monitoring was low, with 38% of diabetics and 27% of CKD individuals undergoing albuminuria testing over 2 years. Twenty-three per cent of the 16 383 individuals satisfying selected KDIGO criteria for nephrology referral visited a nephrologist. Twelve per cent of CKD patients carried an ICD-10 diagnostic code of CKD. CONCLUSIONS: An estimated 6% of the adult Stockholm population accessing healthcare has CKD, but the frequency of albuminuria testing, nephrology consultations and registration of CKD diagnoses was suboptimal despite universal care. Improving provider awareness and treatment of CKD could have a significant public health impact.

Uric acid is not associated with decline in renal function or time to renal replacement therapy initiation in a referred cohort of patients with Stage III, IV and V chronic kidney disease.

BACKGROUND: Although many studies have suggested an association between higher uric acid (UA) and both development of chronic kidney disease (CKD) and faster decline in renal function in Stage I and II CKD, it is not clear whether this effect is consistent throughout higher CKD stages. The aim of this study was to investigate the association between baseline UA and renal outcomes in patients with established CKD (Stages III-V). METHODS: We analysed data in the Swedish Renal Registry-Chronic Kidney Disease (SRR-CKD), which is a nationwide registry of referred CKD patients. Patients with a visit between January 1(st), 2005 and December 31(st), 2011 were followed until initiation of renal replacement therapy (RRT), death, referral to primary care or end of follow-up. Decline in renal function was assessed with a linear mixed model using all estimated glomerular filtration rate (eGFR) assessments recorded during median 28 months of follow-up, adjusting for important confounders such as demographic factors, primary renal disease, age, sex, relevant medication, diet, blood pressure and body mass index. RESULTS: There were 2466 patients with a baseline UA measurement {mean [standard deviation (SD)] of 7.81 [1.98] mg/dL}. The mean decline in renal function was -1.48 (95% CI -1.65; -1.31) mL/min/1.73 m(2) per year. The overall adjusted change in decline in renal function per unit increase in baseline UA was 0.08 (95% CI -0.01; 0.17) mL/min/1.73 m(2) per year indicating no association between higher UA levels and decline in renal function. In Stage III, IV and V CKD patients, the mean decline in renal function was -1.52 (95% CI -1.96; -1.08), -1.52 (95% CI -1.72; -1.32) and -1.19 (95% CI -1.75; -0.64) mL/min/1.73 m(2) per year, respectively. The adjusted change in the decline in renal function per unit increase in baseline UA was -0.09 (95% CI -0.30; 0.13) in Stage III CKD, 0.16 (95% CI 0.04; 0.28) in Stage IV CKD and 0.18 (95% CI -0.09; 0.45) in Stage V CKD. The overall adjusted hazard ratio for start of RRT was 0.97 (95% CI 0.93-1.02). For Stage III, IV and V CKD, it was 0.99 (95% CI 0.73-1.34), 0.97 (95% CI 0.91-1.03) and 0.99 (95% CI 0.91-1.07), respectively. CONCLUSION: UA is not associated with the rate of decline in renal function or time to start of RRT in Stage III, IV and/or V CKD patients.

Validation of insulin sensitivity surrogate indices and prediction of clinical outcomes in individuals with and without impaired renal function.

As chronic kidney disease (CKD) progresses with abnormalities in glucose and insulin metabolism, commonly used insulin sensitivity indices (ISIs) may not be applicable in individuals with CKD. Here we sought to validate surrogate ISIs against the glucose disposal rate by the gold-standard hyperinsulinemic euglycemic glucose clamp (HEGC) technique in 1074 elderly men of similar age (70 years) of whom 495 had and 579 did not have CKD (estimated glomerular filtration rate (eGFR) under 60 ml/min per 1.73 m(2) (median eGFR of 46 ml/min per 1.73 m(2))). All ISIs provided satisfactory (weighted κ over 0.6) estimates of the glucose disposal rate in patients with CKD. ISIs derived from oral glucose tolerance tests (OGTTs) agreed better with HEGC than those from fasting samples (higher predictive accuracy). Regardless of CKD strata, all ISIs allowed satisfactory clinical discrimination between the presence and absence of insulin resistance (glucose disposal rate under 4 mg/kg/min). We also assessed the ability of both HEGC and ISIs to predict all-cause and cardiovascular mortality during a 10-year follow-up. Neither HEGC nor ISIs independently predicted mortality. Adjustment for renal function did not materially change these associations. Thus, ISIs can be applied in individuals with moderately impaired renal function for diagnostic purposes. For research matters, OGTT-derived ISIs may be preferred. Our data do not support the hypothesis of kidney function mediating insulin sensitivity (IS)-associated outcomes nor a role for IS as a predictor of mortality.

Determinants of N-terminal pro-brain natriuretic peptide variation in hemodialysis patients and prediction of survival.

BACKGROUND/AIMS: N-Terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor of cardiac events and death in the general population and in chronic kidney disease. There is limited information on how natriuretic peptides vary in dialysis patients. The aim of this study was to analyze NT-proBNP variability, factors predicting its variability and survival related to NT-proBNP variability. METHODS: A prospective 3-month observational study of prevalent hemodialysis patients with monthly measurements of NT-proBNP was carried out. A total of 211 hemodialysis patients were included, and mortality was recorded during 52 months of follow-up. RESULTS: Inflammation was the strongest predictor of NT-proBNP variability. Patients with constantly high NT-proBNP had an increased risk of death adjusting for age, sex, dialysis vintage and comorbidity but not when also adjusting for nutritional status. CONCLUSIONS: Longitudinal changes in NT-proBNP are associated with changes in inflammation, nutritional status, age and comorbidity. Due to strong interactions with predictors of mortality such as nutritional status, we were unable to confirm NT-proBNP as an independent marker for mortality in dialysis patients.

Macrophage migration inhibitory factor (MIF) and thyroid hormone alterations in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine known to be released from lymphocytes, macrophages and endothelial cells and also in animal models shown to be inducible with glucocorticoids (GC). In contrast, thyroxine seems to antagonize MIF activity. To investigate whether MIF is increased in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and possible correlations with GC dosing and thyroid hormone levels, 27 consecutive patients with active AAV were studied and followed prospectively. Disease activity was assessed using Birmingham Vasculitis Activity Score 2003 (BVAS) at baseline and at follow-up at 3 and 6 months, along with MIF, thyroid hormones free triiodothyronine (fT3) and free thyroxine (fT4), C-reactive protein (CRP) and creatinine. MIF was elevated significantly at baseline compared with follow-up at 3 and 6 months (8,618 pg/mL versus 5,696 and 6,212 respectively; P < 0.002) but did not correlate to CRP, GC dose, creatinine or organ involvement. fT3 was depressed significantly at baseline compared with follow-up (1.99 pg/mL versus 2.31 and 2.67 respectively; P = 0.01) and correlated inversely to the BVAS score at baseline. We found a significant correlation between the MIF/fT4 ratio at baseline versus MIF/fT4 ratio at 6 months (ρ = 0.52, P < 0.005) and a trend between the baseline MIF/fT3 ratio versus MIF/fT3 ratio at 6 months (ρ = 0.39, P = 0.05). These results suggest a possible role for MIF and thyroid status in AAV. Further studies could reveal whether the association between AAV and thyroid hormone levels in the context of elevated MIF may present a link as well as a target of treatment.

Nonthyroidal illness: a risk factor for coronary calcification and arterial stiffness in patients undergoing peritoneal dialysis?

OBJECTIVES: Low triiodothyronine levels, as part of the nonthyroidal illness syndrome, are common in dialysis patients and have repeatedly been shown to be associated with increased (cardiovascular) mortality rates. We hypothesized that increased vascular calcification may mediate this relationship. METHODS: A total of 84 patients from the Stockholm region receiving maintenance peritoneal dialysis were included in the study. Serum concentrations of free triiodothyronine (fT3), thyroxine and thyroid-stimulating hormone were measured. Coronary artery calcium (CAC) scores were assessed by cardiac computed tomography scans. Surrogates of arterial stiffness included aortic diastolic and systolic blood pressures, pulse pressure, augmentation pressure and Buckberg's subendocardial viability ratio measured by pulse waveform analyses. Patients were subsequently followed, and events of death and censoring were recorded. Thyroid hormone concentrations were associated with CAC scores, measures of arterial stiffness and all-cause mortality. The associations between CAC scores and arterial stiffness surrogates and mortality were also determined to evaluate a possible causal pathway. RESULTS: Both CAC scores and arterial stiffness surrogates were substantially higher in individuals with low fT3 levels. These associations persisted in multivariate logistic and linear regression analyses. During a median (interquartile range) follow-up of 32 (22-42) months, 24 patients died. Both fT3 levels below the median value [HR crude 4.1, 95% confidence interval (CI) 1.4-12.6] and CAC scores above the median value (HR crude 5.8, 95% CI 1.7-20.1) were strongly associated with mortality. CONCLUSIONS: In patients undergoing peritoneal dialysis, fT3 levels were strongly associated with arterial stiffness, coronary artery calcification and mortality. We speculate that the association between nonthyroidal illness and mortality may be partly mediated by acceleration of vascular calcification.

Differences in acute metabolism of fructose between hemodialysis patients and healthy subjects.

The consumption of fructose has increased dramatically during the last few decades and parallels the epidemics of obesity, metabolic syndrome, diabetes and chronic kidney disease (CKD). Fructose occurs naturally e.g. in fruit and in honey (rich in this monosaccharide) and as sucrose (table sugar). The effects of fructose have been attributed to the transient increases in serum uric acid levels during its metabolism. Recent research, also in CKD patients, has linked fructose to dysmetabolism of lipids, glucose and oxidative radicals. However, a general consensus of the potentially harmful effects of fructose is lacking. We improved a sensitive inulin assay for fructose measurement in serum and plasma and tested its accuracy in an acute experiment following consumption of pure fructose in controls. In addition, fructose and uric acid were analyzed postprandially during 240 min in six maintenance hemodialysis (HD) patients and nine healthy subjects consuming 190 ml cream/75 g sucrose in a fasting state. Whereas the fructose levels reached a maximum level after 60 min in controls they had not even started to decrease at 240 min in HD-patients. Likewise, while uric acid levels remained stable in controls they increased by 10% in HD patients at 240 min following the meal. In conclusion, a glucose and fat rich meal is associated with delayed absorption and/or metabolism of fructose in HD patients as well as increased serum uric acid levels.

Protein-energy wasting modifies the association of ghrelin with inflammation, leptin, and mortality in hemodialysis patients.

Ghrelin abnormalities contribute to anorexia, inflammation, and cardiovascular risk in hemodialysis patients, leading to worse outcome. However, ghrelin levels are influenced by the nutritional status of the individual. We hypothesized that the consequences of ghrelin alterations in hemodialysis patients are context sensitive and dependent on the presence of protein-energy wasting (PEW). In this cross-sectional study of 217 prevalent hemodialysis patients followed for 31 months, we measured ghrelin, leptin, PEW (subjective global assessment), and C-reactive protein (an index of inflammation). Compared to patients in the middle and upper tertile of ghrelin levels, those in the lowest tertile were older, had higher leptin levels and body mass index, and presented an increased mortality risk that persisted after adjustment for age, gender, and dialysis vintage. This risk was lost after correction for comorbidities. Patients with PEW and low ghrelin values had abnormally high C-reactive protein and leptin by multivariate analysis of variance, and the highest mortality risk compared to non-PEW with high ghrelin from all-cause and cardiovascular-related mortality (adjusted hazard ratios of 3.34 and 3.54, respectively). Low ghrelin values in protein-energy wasted hemodialysis patients were linked to a markedly increased cardiovascular mortality risk. Thus, since these patients were more anorectic, our results provide a clinical scenario where ghrelin therapies may be particularly useful.

High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations.

High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is increasingly recognized as an important proinflammatory mediator actively secreted from monocytes and macrophages and passively released from necrotic cells. In antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), the kidneys are commonly affected vital organs, characterized by focal necrotizing and/or crescentic pauci-immune glomerulonephritis. The aim of the study was to determine whether HMGB1 serum levels are elevated in AAV with renal manifestations. A total of 30 AAV patients (16 female and 14 male; median age 59 years, range 17-82) with Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome with available renal biopsies and serum samples were included. In seven cases, serum was also obtained at rebiopsy in remission. HMGB1 was analyzed with Western blot. Birmingham Vasculitis Activity Score (BVAS, version 2003), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), urinanalysis, creatinine, estimated glomerular filtration rate, sex and age were included in the analysis. Twenty-five episodes of biopsy-proven active disease with BVAS 17.9 ± 4.6 and 13 cases with inactive biopsies and BVAS 2.3 ± 3.7 (P = 0.0001) were identified. CRP, ESR, hematuria and proteinuria were significantly higher in active cases. HMGB1 was significantly elevated (P = 0.01) comparing active with inactive cases (120 ± 48 versus 78 ± 46 ng/mL) and significantly lower in the seven control patients (P = 0.03) at rebiopsy in remission. HMGB1 remained higher in inactive cases compared with historic healthy controls (10.9 ± 10.5 ng/mL). HMGB1 levels did not differ significantly between AAV subgroups. CRP and ESR did not correlate with HMGB1. HMGB1 is significantly increased in AAV with renal involvement. Residual HMGB1 elevation in remission could possibly reflect low-grade inflammatory activity or tissue damage. Future studies may further reveal whether HMGB1 is useful as a marker of disease activity and a predictor of outcome in AAV.

Expression of osteoprotegerin in human fat tissue; implications for chronic kidney disease.

BACKGROUND: Premature vascular calcification (or rather ossification) significantly contributes to morbidity and mortality in patients with chronic kidney disease stage 5 (CKD-5) and is linked to dysregulation of bone remodelling proteins. Recent evidence of a cross-talk between bone and fat tissue urged us to investigate whether the calcification/ossification-associated factors osteoprotegerin (OPG) and alpha-2-HS-glycoprotein (AHSG) are expressed in human uremic subcutaneous adipose tissue (SAT) and if the expression differs from nonuremic SAT. MATERIALS AND METHODS: Abdominal SAT biopsies were obtained from 38 patients with CKD-5 [16 women, 58 (22-73) years old] during the surgical insertion of a peritoneal dialysis catheter and 20 controls [11 females, 56 (40-77) years old] undergoing elective hernia repair or laparoscopic cholecystectomy. Real-time polymerase chain reaction (PCR) quantifications were performed followed by immunohistochemical staining and serum protein concentration measurements. Relative mRNA expression and protein concentrations were evaluated together with clinical parameters. An additional 59 patients with CKD-5 were included for replication of statistical analyses. RESULTS: OPG but not AHSG mRNAs were detected in SAT, which were also positively immunolabelled for OPG. OPG mRNA levels were reduced (P = ·0001) and serum OPG concentrations were elevated (P < 0·0001), both about twofold, in patients compared to controls. Circulating OPG increased in proportion to BMI. CONCLUSIONS: Human SAT expresses OPG but not AHSG, and OPG expression is reduced in patients with CKD-5 when compared to controls, despite increased circulating protein levels.

Trimestral variations of C-reactive protein, interleukin-6 and tumour necrosis factor-α are similarly associated with survival in haemodialysis patients.

BACKGROUND: The impact of intra-individual changes of inflammatory markers [other than C-reactive protein (CRP)] on mortality in haemodialysis (HD) patients is unknown. We therefore studied survival in relation to trimestral variations of CRP, interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). METHODS: In 201 prevalent HD patients from the Mapping of Inflammatory Markers in Chronic Kidney Disease cohort, serum CRP, IL-6 and TNF-α were measured 3 months apart and survival was assessed during follow-up. Based on fluctuations along tertiles of distribution, four patterns were defined for each inflammatory marker: stable low, decrease, increase and stable high. Hazard ratios were calculated by the Cox proportional hazard model, and Pearson's test was used to correlate changes. CRP analyses were replicated in 472 incident HD patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. RESULTS: Patients with persistently elevated CRP values had the worst mortality in crude [HR 2.98 (95% CI 1.71-5.20)] and adjusted [2.79 (1.58-4.94)] Cox models, together with those who increased in their CRP levels [crude 3.27 (1.91-5.60); adjusted 3.13 (1.79-5.45)]. Similar survival patterns were observed for IL-6 and TNF-α variation categories. Correlations among these changes were, however, not strong. In the replication cohort, individuals with persistently elevated CRP values also showed the highest mortality risk [crude 3.38 (2.31-4.94); adjusted 2.33 (1.58-3.45)]. CONCLUSIONS: Trimestral variations of TNF-α, IL-6, and CRP are similarly associated with survival in HD patients. The agreement between changes of these biomarkers was low, suggesting that different pathways may trigger each of these markers.

High-sensitivity troponins in dialysis patients: variation and prognostic value.

BACKGROUND: Dialysis patients have a high prevalence of cardiovascular mortality but also elevated cardiac troponins (cTns) even without signs of cardiac ischaemia. The study aims to assess variation and prognostic value of high-sensitivity cTnI and cTnT in prevalent dialysis patients. METHODS: In 198 prevalent haemodialysis (HD) and 78 peritoneal dialysis (PD) patients, 4-monthly serum troponin I and T measurements were obtained. Reference change values (RCVs) were used for variability assessment and competing-risk regression models for survival analyses; maximal follow-up was 50 months. RESULTS: HD and PD patients had similar troponin levels [median (interquartile range) troponin I: 25 ng/L (14-43) versus 21 ng/L (11-37), troponin T: 70 ng/L (44-129) versus 67 ng/L (43-123)]. Of troponin I and T levels, 42% versus 98% were above the decision level of myocardial infarction. RCVs were +68/-41% (troponin I) and +29/-23% (troponin T). Increased variability of troponins related to higher age, male sex, protein-energy wasting and congestive heart failure, but not ischaemic heart disease or dialysis form. Elevated troponin T, but not troponin I, predicted death after adjusting for confounders. CONCLUSIONS: A large proportion of prevalent dialysis patients without current established or ongoing cardiac events have elevated levels of high-sensitivity cTns. Mortality risk was doubled in patients with persistently high troponin T levels. The large intraindividual variation of cTns suggests that serial measurements and reference change levels may be used to improve diagnostic utility. However, evidence-based recommendations require more data from large studies of dialysis patients with cardiac events.

Variations in C-reactive protein during a single haemodialysis session do not associate with mortality.

BACKGROUND: An increase in C-reactive protein (CRP) levels during a single haemodialysis (HD) session has been associated with mortality. These associations, however, are difficult to understand from the current understanding of CRP metabolism. METHODS: In 190 Swedish haemodialysis (HD) patients from the Mapping of Inflammatory Markers in Chronic Kidney Disease (MIMICK) cohort, CRP was measured before and after a HD session. During follow-up, events of death and censoring were recorded, and hazard ratios were calculated and analysed as a function of CRP variation. Results were replicated in 94 Dutch HD patients from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD). In this cohort, also correlation and kappa statistics were calculated to assess concordance in CRP changes amid multiple dialysis sessions from the same individuals. RESULTS: In both cohorts, mean CRP values did not increase during a single HD session. In the MIMICK, median (interquartile range) dialysis vintage was 29.0 (14.8-57.0) months. In both crude [hazard ratio (95% confidence interval): 1.008 (0.971-1.047)] and multivariate Cox models [0.996 (0.949-1.046)], no association was observed with mortality. In the NECOSAD, individuals endured 6.0 (6.0-12.0) months on dialysis. No association was found with mortality neither in a crude [0.961 (0.908-1.018)] nor in an adjusted analysis [0.978 (0.923-1.037)]. Finally, the concordance between changes in different sessions was poor. CONCLUSIONS: CRP changes during a single HD session do not associate with mortality, thereby adding to the biological uncertainty concerning the ability of CRP to rise in such a short period.

Visfatin is increased in chronic kidney disease patients with poor appetite and correlates negatively with fasting serum amino acids and triglyceride levels.

OBJECTIVE: Anorexia is a common complication of chronic kidney disease (CKD), while novel animal and human data suggest a role for visfatin in regulating feeding behavior. We hypothesized that increased visfatin levels in CKD patients may be involved in the regulation of appetite and nutrient homeostasis. METHODS: This is a cross-sectional study where circulating visfatin levels were analysed in 246 incident CKD stage 5 patients starting dialysis therapy. The associations between visfatin (enzyme-linked immunosorbent assay, ELISA) and anthropometric and biochemical nutritional status, self-reported appetite, fasting serum amino acids (high-performance liquid chromatography) and circulating cytokine levels (ELISAs) were assessed. We also performed genotyping (Pyrosequencing(R)) of two polymorphisms (rs1319501 and rs9770242) in the visfatin gene. RESULTS: Serum visfatin concentrations were not associated with either body mass index or serum leptin. Across groups with worsening appetite, median visfatin levels were incrementally higher (P < 0.05). With increasing visfatin tertiles, patients proved to be more often anorectic (P < 0.05) and to have incrementally lower serum albumin, cholesterol and triglycerides as well as lower essential and non-essential serum amino acids (P < 0.05 for all). A polymorphism in the visfatin gene was associated with increased circulating visfatin levels and, at the same time, a higher prevalence of poor appetite (P < 0.05 for both). CONCLUSION: Our study suggests novel links between visfatin and anorexia in CKD patients. Based on recent studies, we speculate that high visfatin in CKD patients may constitute a counter-regulatory response to central visfatin resistance in uremia. Future studies should examine a putative role of visfatin as a regulator of nutrient homeostasis in uremia.