Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD.

BACKGROUND AND HYPOTHESIS: Dysregulated energy metabolism is a recently discovered key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate concentrations are associated with reduced disease progression in patients with ADPKD. METHODS: We analyzed data from 670 patients with ADPKD participating in the DIPAK cohort, a multi-center prospective observational cohort study. Beta-hydroxybutyrate was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting, or had missing beta-hydroxybutyrate levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. RESULTS: Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 (IQR 495-1327) ml/m, and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73m2. The median concentration of beta-hydroxybutyrate was 94 (IQR 68-147) µmol/L. Cross-sectionally, beta-hydroxybutyrate was neither associated with eGFR nor with htTKV. Longitudinally, beta-hydroxybutyrate was positively associated with eGFR slope (B = 0.35 ml/min/1.73m2 (95% CI 0.09 to 0.61), p = 0.007), but not with kidney growth. After adjustment for potential confounders, every doubling in beta-hydroxybutyrate concentration was associated with an improvement in the annual rate of eGFR by 0.33 ml/min/1.73m2 (95% CI 0.09 to 0.57, p = 0.008). CONCLUSION: These observational analyses support the hypothesis that interventions that raise beta-hydroxybutyrate concentration could reduce the rate of kidney function decline in patients with ADPKD.

Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease: the AGAINST-PLD study.

BACKGROUND: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD. METHODS: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE). DISCUSSION: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 .

Long-term efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease, on dialysis or after kidney transplantation: a national prospective observational cohort study.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

[Proton pump inhibitor-induced nephrotoxicity]. / Nefrotoxiciteit van protonpompremmers.

Proton pump inhibitors are widely used, and generally considered safe. In this clinical lesson two cases are presented with a strong suspicion of proton pump inhibitor induced decline of kidney function. This adverse event has only recently been identified in epidemiological studies. Our cases illustrate that chronic proton pump inhibitor nephrotoxicity can manifest subtle and may therefore be difficult to recognize. We discuss the current epidemiological evidence to support these observations, and the pathophysiology and clinical manifestations of proton pump inhibitor nephrotoxicity. In case a subject using a proton pump inhibitor shows kidney function decline, without a clear cause, withdrawal of this medication is advised. Although for an individual patient the risk may not be high, the large number of proton pump users makes that this adverse event is important on a population level.

GlycA, a novel pro-inflammatory glycoprotein biomarker is associated with mortality: results from the PREVEND study and meta-analysis.

BACKGROUND: Chronic diseases are associated with an inflammatory response. We determined the association of two inflammatory markers, GlycA and high-sensitivity C-reactive protein (hsCRP), with overall and cause-specific mortality in a cohort of men and women. METHODS: Cox regression analyses were used to examine associations of GlycA and hsCRP with all-cause, cancer and cardiovascular mortality in 5526 subjects (PREVEND cohort; average follow-up 12.6 years). RESULTS: GlycA was associated with all-cause mortality (n = 838), independent of clinical risk factors and hsCRP (hazard ratio 1.43 [95% confidence interval (CI): 1.09-1.87] for top versus bottom quartiles). For hsCRP, the association with all-cause mortality was nonsignificant after adjustment for GlycA. GlycA and hsCRP were associated with cancer mortality in men (n = 248), but not in women (n = 132). Neither GlycA nor hsCRP was independently associated with cardiovascular mortality (n = 201). In a meta-analysis of seven population-based studies, including 8153 deaths, the pooled multivariable-adjusted relative risk of GlycA for all-cause mortality was 1.74 (95% CI: 1.40-2.17) for top versus bottom quartiles. The association of GlycA with all-cause mortality was somewhat stronger than that of hsCRP. GlycA and hsCRP were not independently associated with cardiovascular mortality. The associations of GlycA and hsCRP with cancer mortality were present in men, but not in women. CONCLUSIONS: GlycA is significantly associated with all-cause mortality. GlycA and hsCRP were each not independently associated with cardiovascular mortality. The association of GlycA and hsCRP with cancer mortality appears to be driven by men.

Correction to: Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

The values given for copeptin levels in men in quartiles 1 and 2 (Table 1) were incorrect, and should have read.

Treatable Vascular Risk and Cognitive Performance in Persons Aged 35 Years or Older: Longitudinal Study of Six Years.

BACKGROUND: Poor cognitive performance is associated with high vascular risk. However, this association is only investigated in elderly. As neuropathological changes precede clinical symptoms of cognitive impairment by several decades, it is likely that cognitive performance is already associated with vascular risk at middle-age. OBJECTIVES: To investigate the association of cognitive performance with treatable vascular risk in middle-aged and old persons. DESIGN: Longitudinal study with three measurements during follow-up period of 5.5 years. SETTING: City of Groningen, the Netherlands. PARTICIPANTS: Cohort of 3,572 participants (age range, 35-82 years; mean age, 54 years; men, 52%). EXPOSURE: Treatable vascular risk as defined by treatable components of the Framingham Risk Score for Cardiovascular Disease at the first measurement (diabetes mellitus, smoking, hypercholesterolemia and hypertension). MEASUREMENTS: Change in cognitive performance during follow-up. Cognitive performance was measured with Ruff Figural Fluency Test (RFFT) and Visual Association Test (VAT), and calculated as the average of the standardized RFFT and VAT score per participant. RESULTS: The mean (SD) cognitive performance changed from 0.00 (0.79) at the first measurement to 0.15 (0.83) at second measurement and to 0.39 (0.82) at the third measurement (Ptrend<0.001). This change was negatively associated with treatable vascular risk: the change in cognitive performance between two measurements decreased with 0.004 per one-point increment of treatable vascular risk (95%CI, -0.008 to 0.000; P=0.05) and with 0.006 per one-year increment of age (95%CI, -0.008 to -0.004; P<0.001). CONCLUSIONS: Change in cognitive performance was associated with treatable vascular risk in persons aged 35 years or older.

Clinical predictors of escalating care in hepatic and renal cyst infection in autosomal dominant polycystic kidney and liver disease.

BACKGROUND: Cyst infection may occur in autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD). Antimicrobial agents often fail to control infection, leading to invasive action. We aimed to identify factors predicting escalation of care. METHODS: ADPKD and ADPLD patients were identified from local/national databases (2001-2013). Records were screened for patients meeting criteria for cyst infection (positive cyst aspirate and/or clinical findings). Factors that predict escalated care were identified with multivariate modified Poisson regression. RESULTS: We screened 1773 patients. A total of 77 patients with cyst infection (4.3%) were included for analysis (hepatic 36%; male 49%; age 54 ±; 13 years; ADPKD 95%; dialysis 9%, diabetes 18%, renal transplant 56%, eGFR [IQR 24-78] ml/min/1.73 m2 (excluding patients with a history of renal transplant or receiving dialysis)). A pathogen was identified in 71% of cases. Escherichia coli was the most common pathogen and accounted for 69% of cases. Initial treatment was limited to antibiotics in 87% of patients (n = 67), 40% included a fluoroquinolone. Ultimately, 48% of patients underwent some form of invasive action (escalation of care). Increasing white blood cell count (WBC) (RR 1.04 95%-CI 1.01-1.07, p = 0.008) was associated with escalating care, whereas an increase in time between transplant and infection (RR 0.92 95% CI 0.86-0.97, p = 0.005) and E. coli isolation (RR 0.55 95% CI 0.34-0.89, p = 0.02) were protective. CONCLUSION: High serum WBC, isolation of atypical pathogens and early infection after transplantation are factors that increase the risk of escalation of care in hepatic and renal cyst infection patients.

[Autosomal dominant polycystic kidney disease: should patients' young adult relatives be screened or not?] / Familiaire cystenieren: jongvolwassen familieleden screenen of niet?

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, with a global prevalence of 10 per 10,000. It is characterized by the formation of numerous cysts in both kidneys, and leads to renal function loss; the majority of patients will eventually need renal replacement therapy. It is possible to screen patients' presymptomatic family members from a young age, but this has not historically been recommended as until recently there were no treatment options. This year, the vasopressin V2 receptor antagonist tolvaptan was approved for prescription in ADPKD, to slow the rate of renal function decline. The availability of this new treatment option, along with other factors such as the possible use of IVF procedures with pre-implantation genetic diagnosis, imply that we have to rethink the issue of presymptomatic screening. Young adults at-risk should be screened, to give them the chance to opt for treatment.

[Asymptomatic microscopic haematuria: usually not a problem]. / Asymptomatische microscopische hematurie.

Asymptomatic microscopic haematuria is a common finding and can have many different causes. Only a small fraction of patients referred for microscopic haematuria have an underlying urological malignancy or serious nephrogenic disease. It is important that only those patients with microscopically confirmed microscopic haematuria are referred. Often no cause can be found even after thorough diagnostic work-up. The work-up of microscopic haematuria can include urethrocystoscopy, ultrasound, multi-phase CT and cytology. These procedures are not only costly, but can have associated health risks and may also cause patients anxiety and distress. There is no evidence to support the hypothesis that microscopic haematuria is the precursor of macroscopic haematuria, which is significantly more likely to have serious underlying causes. A diagnostic work-up should be initiated with caution.

Trajectories of metabolic risk factors and biochemical markers prior to the onset of type 2 diabetes: the population-based longitudinal Doetinchem study.

BACKGROUND: Risk factors often develop at young age and are maintained over time, but it is not fully understood how risk factors develop over time preceding type 2 diabetes. We examined how levels and trajectories of metabolic risk factors and biochemical markers prior to diagnosis differ between persons with and without type 2 diabetes over 15-20 years. METHODS: A total of 355 incident type 2 diabetes cases (285 self-reported, 70 with random glucose ⩾11.1 mmol l-1) and 2130 controls were identified in a prospective cohort between 1987-2012. Risk factors were measured at 5-year intervals. Trajectories preceding case ascertainment were analysed using generalised estimating equations. RESULTS: Among participants with a 21-year follow-up period, those with type 2 diabetes had higher levels of metabolic risk factors and biochemical markers 15-20 years before case ascertainment. Subsequent trajectories were more unfavourable in participants with type 2 diabetes for body mass index (BMI), HDL cholesterol and glucose (P<0.01), and to a lesser extent for waist circumference, diastolic and systolic blood pressure, triglycerides, alanine aminotransferase, gamma glutamyltransferase, C-reactive protein, uric acid and estimated glomerular filtration rate compared with participants without type 2 diabetes. Among persons with type 2 diabetes, BMI increased by 5-8% over 15 years, whereas the increase among persons without type 2 diabetes was 0-2% (P<0.01). The observed differences in trajectories of metabolic risk factors and biochemical markers were largely attenuated after inclusion of BMI in the models. Results were similar for men and women. CONCLUSIONS: Participants with diabetes had more unfavourable levels of metabolic risk factors and biochemical markers already 15-20 years before diagnosis and worse subsequent trajectories than others. Our results highlight the need, in particular, for maintenance of a healthy weight from young adulthood onwards for diabetes prevention.

Feasibility of measuring renal blood flow by phase-contrast magnetic resonance imaging in patients with autosomal dominant polycystic kidney disease.

OBJECTIVES: Renal blood flow (RBF) has been shown to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). We investigated the feasibility and accuracy of phase-contrast RBF by MRI (RBFMRI) in ADPKD patients with a wide range of estimated glomerular filtration rate (eGFR) values. METHODS: First, we validated RBFMRI measurement using phantoms simulating renal artery hemodynamics. Thereafter, we investigated in a test-set of 21 patients intra- and inter-observer coefficient of variation of RBFMRI. After validation, we measured RBFMRI in a cohort of 91 patients and compared the variability explained by characteristics indicative for disease severity for RBFMRI and RBF measured by continuous hippuran infusion. RESULTS: The correlation in flow measurement using phantoms by phase-contrast MRI was high and fluid collection was high (CCC=0.969). Technical problems that precluded RBFMRI measurement occurred predominantly in patients with a lower eGFR (34% vs. 16%). In subjects with higher eGFRs, variability in RBF explained by disease characteristics was similar for RBFMRI compared to RBFHip, whereas in subjects with lower eGFRs, this was significantly less for RBFMRI. CONCLUSIONS: Our study shows that RBF can be measured accurately in ADPKD patients by phase-contrast, but this technique may be less feasible in subjects with a lower eGFR. KEY POINTS: Renal blood flow (RBF) can be accurately measured by phase-contrast MRI in ADPKD patients. RBF measured by phase-contrast is associated with ADPKD disease severity. RBF measurement by phase-contrast MRI may be less feasible in patients with an impaired eGFR.

Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus.

AIMS: Early detection of individuals with Type 2 diabetes mellitus or hypertension at risk for micro- or macroalbuminuria may facilitate prevention and treatment of renal disease. We aimed to discover plasma and urine metabolites that predict the development of micro- or macroalbuminuria. METHODS: Patients with Type 2 diabetes (n = 90) and hypertension (n = 150) were selected from the community-cohort 'Prevention of REnal and Vascular End-stage Disease' (PREVEND) and the Steno Diabetes Center for this case-control study. Cases transitioned in albuminuria stage (from normo- to microalbuminuria or micro- to macroalbuminuria). Controls, matched for age, gender, and baseline albuminuria stage, remained in normo- or microalbuminuria stage during follow-up. Median follow-up was 2.9 years. Metabolomics were performed on plasma and urine. The predictive performance of a metabolite for albuminuria transition was assessed by the integrated discrimination index. RESULTS: In patients with Type 2 diabetes with normoalbuminuria, no metabolites discriminated cases from controls. In patients with Type 2 diabetes with microalbuminuria, plasma histidine was lower (fold change = 0.87, P = 0.02) and butenoylcarnitine was higher (fold change = 1.17, P = 0.007) in cases vs. controls. In urine, hexose, glutamine and tyrosine were lower in cases vs. controls (fold change = 0.20, P < 0.001; 0.32, P < 0.001; 0.51, P = 0.006, respectively). Adding the metabolites to a model of baseline albuminuria and estimated glomerular filtration rate metabolites improved risk prediction for macroalbuminuria transition (plasma integrated discrimination index = 0.28, P < 0.001; urine integrated discrimination index = 0.43, P < 0.001). These metabolites did not differ between hypertensive cases and controls without Type 2 diabetes. CONCLUSIONS: Type 2 diabetes-specific plasma and urine metabolites were discovered that predict the development of macroalbuminuria beyond established renal risk markers. These results should be confirmed in a large, prospective cohort.

High fall incidence and fracture rate in elderly dialysis patients.

BACKGROUND: Although it is recognised that the dialysis population is ageing rapidly, geriatric complications such as falls are poorly appreciated, despite the many risk factors for falls in this population. The objective of this study was to determine the incidence, complications and risk factors for falls in an elderly dialysis population. METHODS: A one-year observational study of chronic dialysis patients aged ≥ 70 years. At baseline, patient characteristics were noted and during follow-up the vital parameters and laboratory values were recorded. Patients were questioned weekly about falls, fall circumstances and consequences by trained nurses. RESULTS: 49 patients were included with a median age of 79.3 years (70-89 years). During follow-up 40 fall accidents occurred in 27 (55%) patients. Falls resulted in fractures in 15% of cases and in hospital admissions in 15%. In haemodialysis (HD) patients, the mean systolic blood pressure (SBP) before HD was lower in fallers compared with non-fallers (130 vs. 143 mmHg). Several patients in the lower blood pressure category received antihypertensive medication. For every 5 mmHg lower SBP (before HD) the fall risk increased by 30% (hazard ratio (HR) 1.30, 95% CI 1.03-1.65, p = 0.03). Furthermore, fall risk increased by 22% for every 10 pmol/l rise of parathyroid hormone (HR 1.22, 95% CI 1.06-1.39, p = 0.004). CONCLUSIONS: Elderly dialysis patients have a high incidence of falls accompanied by a high fracture rate. Given the high complication rate, elderly patients at risk of falling should be identified and managed. Reduction of blood pressure-lowering medication might be a treatment strategy to reduce falls.

Telomere length loss due to smoking and metabolic traits.

OBJECTIVES: Human age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length. DESIGN AND METHODS: Leucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time-points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16 783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics. RESULTS: We observed an average attrition rate of 0.47 ± 0.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39-60) years at baseline. Annual telomere attrition rate increased with age (P < 0.001) and was faster on average in men than in women (P for interaction 0.043). The major independent factors determining telomere attrition rate were active smoking (approximately tripled the loss of RTLU per year, P < 0.0001) and multiple traits of the metabolic syndrome (waist-hip ratio, P = 0.007; blood glucose level, P = 0.045, and HDL cholesterol level, P < 0.001). CONCLUSIONS: Smoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases.

Stability of creatinine and cystatin C in whole blood.

BACKGROUND: As yet little is known about the effect of delayed separation of whole blood stored at room temperature on the stability of the kidney function markers creatinine and cystatin C. METHODS: We used plasma samples of 45 patients with a wide range of creatinine and cystatin C concentration. Samples were sent by post as whole blood, and differences in creatinine and cystatin C concentrations when measured (by enzymatic assay and PETIA, respectively) in plasma separated shortly after blood withdrawal or in plasma obtained after delayed separation at 24, 48 and 72 h. Intra- and inter-assay variability was assessed and total change limit was calculated to assess analyte stability. RESULTS: Total change limit was 3.3% for creatinine and 3.9% for cystatin C. In whole blood creatinine and cystatin C remained stable up to 48 h. Delayed separation of whole blood did not induce more variability in measured concentrations of both analytes. Glomerular filtration rate estimated with the CKD-EPI equations showed less than 3 mL/min/1.73 m² difference when using creatinine or cystatin C concentration measured in plasma separated up to 48 h after blood withdrawal compared to plasma separated shortly after blood withdrawal. The new CKD-EPI equation that uses creatinine as well as cystatin C to estimate GFR showed even at 72 h less than 3 mL/min/1.73 m² difference. CONCLUSIONS: Creatinine and cystatin C remain stable in whole blood stored at room temperature up to 48 h before separation, and changes in these analytes during this time period do not affect variability and eGFR.

Copeptin, a surrogate marker for arginine vasopressin, is associated with declining glomerular filtration in patients with diabetes mellitus (ZODIAC-33).

AIM/HYPOTHESIS: Arginine vasopressin (AVP), the hormone important for maintaining fluid balance, has been shown to cause kidney damage in rodent models of diabetes. We investigated the potential role of AVP in the natural course of kidney function decline in diabetes in an epidemiological study. METHODS: Plasma copeptin, a surrogate for AVP, was measured in baseline samples from patients with type 2 diabetes treated in primary care and included in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort. RESULTS: Samples from 1,328 patients were available; 349 were analysed separately because they used renin-angiotensin-aldosterone system inhibition (RAASi), which influences albumin/creatinine ratio (ACR) and estimated (e)GFR. In the other 979 patients (46% men, age 68 years [58-75], ACR 1.8 mg/mmol [0.9-5.7], eGFR 67 ± 14 ml min(-1) 1.73 m(-2)) baseline copeptin (5.3 pmol/l [3.2-9.5]) was significantly associated with log e [ACR] and eGFR, even after adjustment for sex, age and risk factors for kidney function decline (standardised [std] ß 0.13, p < 0.001, std ß -0.20, p < 0.001 respectively). Follow-up data were available for 756 patients (6.5 years [4.1-9.6]). Baseline copeptin was associated with increase in ACR (std ß 0.09, p = 0.02), but lost significance after adjustment (std ß 0.07, p = 0.08). Copeptin was associated with a decrease in eGFR after adjustment (std ß -0.09, p = 0.03). The strength of the association of copeptin with change in eGFR was stronger than that of established risk factors for kidney function decline (e.g. BMI, HbA1c). In patients who used RAASi there was a significant association between baseline copeptin and ACR and eGFR, but not with change in ACR and eGFR. CONCLUSIONS/INTERPRETATION: In patients with diabetes not using RAASi a higher baseline copeptin concentration is significantly associated with higher baseline ACR and lower eGFR values and with a decline in eGFR during follow-up. This last association is independent of, and stronger than, most traditional risk factors for kidney function decline.

A urinary peptide biomarker set predicts worsening of albuminuria in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Microalbuminuria is considered the first clinical sign of kidney dysfunction and is associated with a poor renal and cardiovascular prognosis in type 2 diabetes. Detection of patients who are prone to develop micro- or macroalbuminuria may represent an effective strategy to start or optimise therapeutic intervention. Here we assessed the value of a urinary proteomic-based risk score (classifier) in predicting the development and progression of microalbuminuria. METHODS: We conducted a prospective case-control study. Cases (n = 44) and controls (n = 44) were selected from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study and from the Steno Diabetes Center (Gentofte, Denmark). Cases were defined by transition from normo- to microalbuminuria or from micro- to macroalbuminuria over a follow-up of 3 years. Controls with no transitions in albuminuria were pair-matched for age, sex and albuminuria status. A model for the progression of albuminuria was built using a proteomic classifier based on 273 urinary peptides. RESULTS: The proteomic classifier was independently associated with transition to micro- or macroalbuminuria (OR 1.35 [95% CI 1.02, 1.79], p = 0.035). The classifier predicted the development and progression of albuminuria on top of albuminuria and estimated GFR (eGFR, area under the receiver operating characteristic [ROC] curve increase of 0.03, p = 0.002; integrated discrimination index [IDI]: 0.105, p = 0.002). Fragments of collagen and α-2-HS-glycoprotein showed significantly different expression between cases and controls. CONCLUSIONS/INTERPRETATION: Although limited by the relatively small sample size, these results suggest that analysis of a urinary biomarker set enables early renal risk assessment in patients with diabetes. Further work is required to confirm the role of urinary proteomics in the prevention of renal failure in diabetes.

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women.

Insulin resistance and risk of venous thromboembolism: results of a population-based cohort study.

BACKGROUND: Obesity is an established risk factor for venous thromboembolism (VTE), but it is uncertain how this is mediated. Insulin resistance has a central role in the pathophysiology of the metabolic effects of obesity. OBJECTIVE: We aimed to investigate whether insulin resistance is a risk factor for VTE. METHODS: For this analysis we used the PREVEND prospective community-based observational cohort study. Insulin resistance was measured as HOMA-IR (homeostasis model assessment of insulin resistance) and fasting insulin. VTE was assessed using databases of the national registries of hospital discharge diagnoses, death certificates and the regional anticoagulation clinic. RESULTS: Out of 7393 subjects, 114 developed VTE during a median follow-up of 10.5 years. High HOMA-IR was associated with increased risk of VTE after adjustment for traditional cardiovascular risk factors, CRP and markers of endothelial dysfunction (hazard ratio [HR], 1.38; 95% confidence interval [95% CI], 1.09-1.75; P=0.007). When body mass index (BMI) was added to the model, BMI was a strong risk predictor for VTE (HR, 1.53; 95% CI, 1.24-1.88; P<0.001) whereas HOMA-IR no longer showed such an association (HR, 1.11; 95% CI, 0.85-1.43; P=0.45). Results were similar for fasting insulin. CONCLUSION: Our population-based cohort study shows an increased risk of VTE in subjects with increasing insulin resistance but not independently of BMI.