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1.  Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes in both general and high-risk populations 
Kidney international  2011;80(1):93-104.
Both low eGFR and albuminuria are known risk factors for ESRD. This paper focuses on their joint contribution to ESRD and other kidney outcomes.
We performed a collaborative meta-analysis of 9 general population cohorts with 845,125 participants and 8 cohorts with 173,892 participants selected because of high risk for chronic kidney disease. Both eGFR and albuminuria were tested as risk factors for ESRD, acute kidney injury and progressive chronic kidney disease.
In general population cohorts, the risk for ESRD was unrelated to eGFR at values 75–105 ml/min/1.73m2 and increased exponentially at lower eGFR. Hazard ratios (95% confidence interval) at eGFR 60, 45, and 15 (versus 95) ml/min/1.73m2 were 3.69 (2.36–5.76), 29.3 (19.5–44.1) and 454.9 (112.4–1840.2), respectively, after adjustment for albumin-to-creatinine ratio and cardiovascular risk factors. Albuminuria was associated with ESRD risk linearly without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios 30, 300 and 1000 (versus 5) mg/g were 4.87 (2.30–10.3), 13.4 (5.49–32.7) and 28.4 (14.9–54.2), respectively. eGFR and albuminuria were multiplicatively associated with ESRD, without evidence for interaction. Similar, but numerically less pronounced associations were observed for acute kidney injury and progressive chronic kidney disease. The findings in high risk cohorts were generally comparable to those in general population cohorts.
In conclusion, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive chronic kidney disease independent of each other and of cardiovascular risk factors, both in the general population and high risk cohorts.
PMCID: PMC3959732  PMID: 21289597
Meta-analysis; eGFR (kidney function); albumin-to-creatinine ratio (albuminuria); dipstick (proteinuria); ESRD (end-stage renal disease); acute kidney injury; progressive chronic kidney disease
2.  Hypertension and Low HDL-Cholesterol were Associated with Reduced Kidney Function Across the Age Spectrum: A Collaborative Study 
Annals of epidemiology  2013;23(3):106-111.
To determine if the associations among established risk factors and reduced kidney function vary by age.
We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.
Hypertension and low HDL-cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.
Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults.
PMCID: PMC3570601  PMID: 23313266
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking
3.  Relationship of Copeptin, a Surrogate Marker for Arginine Vasopressin, With Change in Total Kidney Volume and GFR Decline in Autosomal Dominant Polycystic Kidney Disease: Results From the CRISP Cohort 
Experimental studies indicate that arginine vasopressin (AVP) may have deleterious effects in the pathogenesis of ADPKD. The significance of AVP in human ADPKD, however, is yet unclear.
Study design
Longitudinal, observational study with 8.5 (IQR, 7.7-9.0) years follow-up (CRISP; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease).
Setting & Participants
241 ADPKD patients with creatinine clearance >70 mL/min.
Plasma copeptin concentration, a surrogate marker for vasopressin.
Change in measured glomerular filtration rate (mGFR, assessed by iothalamate clearance), and total kidney volume (TKV, measured by MRI).
Baseline copeptin, plasma and urinary osmolality, and measurements of TKV and mGFR during follow-up.
In these patients (median age, 34; [IQR, 25-40] years; 38% male; median mGFR, 94 [IQR, 79-145] mL/min/1.73 m2; median total kidney volume, 859 [IQR, 577-1299] mL) median copeptin level was 2.9 (IQR, 1.8-5.1) pmol/L. Copeptin was not associated with plasma osmolality (p=0.3), the physiologic stimulus for AVP release, but was significantly associated with change in TKV during follow-up (p<0.001). This association remained significant after adjusting for gender, age, cardiovascular risk factors and diuretic use (p=0.03). Copeptin level was borderline significantly associated with change in mGFR after adjusting for these variables (p=0.09).
No standardization of hydration status at time of copeptin measurement.
These data show that in ADPKD copeptin levels, as a marker for AVP, are not correlated with plasma osmolality. Most importantly, high copeptin levels are independently associated with disease progression in early ADPKD. This is in line with experimental studies that indicate a disease-promoting role for AVP.
PMCID: PMC3574620  PMID: 23089511
4.  Age and the Association of Kidney Measures with Mortality and End-Stage Renal Disease 
Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.
To evaluate possible effect modification (interaction) of age on the association of estimated GFR and albuminuria with clinical risk examining both relative and absolute risk.
Design, Setting, Participants
We investigated 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australesia, Europe, and North/South America conducted during 1972–2011 with mean follow-up time of 5.8 years (range 0–31 years).
Main Outcome Measures
Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholestserol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates.
Mortality (112,325 deaths) and ESRD (8,411 events) risk were higher at lower eGFR and higher albuminuria in every age category. In general/high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age: e.g., adjusted HRs (95% CI) at eGFR 45 vs. 80 ml/min/1.73m2 were 3.50 (2.55–4.81), 2.21 (2.02–2.41), 1.59 (1.42–1.77), and 1.35 (1.23–1.48) in age categories 18–54, 55–64, 65–74 and 75+ years, respectively (P-values for age interaction <0.05). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0–12.8], 12.2 [10.3–14.3], 13.3 [9.0–18.6], and 27.2 [13.5–45.5] excess deaths per 1,000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age were less evident, while differences in absolute risk were higher in the older age categories (7.5 [95% CI, 4.3–11.9], 12.2 [7.9–17.6], 22.7 [15.3–31.6], and 34.3 [19.5–52.4] excess deaths per 1,000 person-years, respectively by age category, at ACR 300 mg/g compared to 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories.
Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risks differences at older age.
PMCID: PMC3936348  PMID: 23111824
5.  The Interaction of Age and Type 2 Diabetes on Executive Function and Memory in Persons Aged 35 Years or Older 
PLoS ONE  2013;8(12):e82991.
It is generally assumed that type 2 diabetes increases the risk of cognitive dysfunction in old age. As type 2 diabetes is frequently diagnosed before the age of 50, diabetes-related cognitive dysfunction may also occur before the age of 50. Therefore, we investigated the association of type 2 diabetes with cognitive function in people aged 35–82 years. In a cross-sectional study comprising 4,135 participants of the Prevention of Renal and Vascular ENd-stage Disease study (52% men; mean age (SD), 55 (12) years) diabetes was defined according to the criteria of the American Diabetes Association. Executive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0 points; best score, 175 points), and memory was measured with the Visual Association Test (VAT; worst score, 0 points; best score, 12 points). The association of diabetes with cognitive function was investigated with multiple linear or, if appropriate, logistic regression analysis adjusting for other cardiovascular risk factors and APOE ε4 carriership. Type 2 diabetes was ascertained in 264 individuals (6%). Persons with diabetes had lower RFFT scores than persons without diabetes: mean (SD), 51 (19) vs. 70 (26) points (p<0.001). The difference in RFFT score was largest at age 35–44 years (mean difference 32 points; 95% CI, 15 to 49; p<0.001) and gradually decreased with increasing age. The association of diabetes with RFFT score was not modified by APOE ε4 carriership. Similar results were found for VAT score as outcome measure although these results were only borderline statistically significant (p≤0.10). In conclusion, type 2 diabetes was associated with cognitive dysfunction, especially in young adults. This was independent of other cardiovascular risk factors and APOE ε4 carriership.
PMCID: PMC3867457  PMID: 24367577
6.  Comparison of risk prediction using the CKD-EPI equation and the MDRD Study equation for estimated glomerular filtration rate 
JAMA : the journal of the American Medical Association  2012;307(18):10.1001/jama.2012.3954.
The CKD-EPI equation more accurately estimates glomerular filtration rate (eGFR) than the MDRD Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking.
To evaluate risk implications of eGFRCKD-EPI compared to eGFRMDRD in populations with a broad range of demographic and clinical characteristics.
Design, Setting, and Participants
Meta-analyses based on data from 1,130,472 adults (aged 18 years or older) from 25 general population, 7 high-risk (of vascular disease), and 13 chronic kidney disease (CKD) cohorts. Data transfer and analyses were conducted between March 2011 and March 2012.
Main Outcome Measures
All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7,644 events from 21 cohorts) during 9.4 million person-years of follow-up (median of mean follow-up time across cohorts was 7.4 years).
eGFR was classified into six categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 ml/min/1.73m2) by both equations. Compared to eGFRMDRD, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower eGFR category by the CKD-EPI equation, respectively, and the prevalence of CKD stage 3-5 (eGFR <60 ml/min/1.73m2) was reduced from 8.7% to 6.3%. 34.7% of participants with eGFRMDRD 45-59 were reclassified to eGFRCKD-EPI 60-89 and had lower incidence rates (per 1,000 person-years) of outcomes compared to those not reclassified (9.9 vs. 34.5 for all-cause mortality, 2.7 vs. 13.0 for cardiovascular mortality, and 0.5 vs. 0.8 for ESRD). The corresponding adjusted hazard ratios were 0.80 (95% confidence interval, 0.74 to 0.86) for all-cause mortality, 0.73 (0.65 to 0.82) for cardiovascular mortality, and 0.49 (0.27 to 0.88) for ESRD. Similar findings were observed in other eGFRMDRD categories. Net reclassification improvement (NRI) based on eGFR categories was significantly positive for all outcomes (range from 0.06 to 0.13, all P<0.001). NRI was similarly positive in most subgroups defined by age (< and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in high-risk and CKD cohorts were largely consistent with the general population cohorts.
The CKD-EPI equation classified fewer individuals as CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.
PMCID: PMC3837430  PMID: 22570462
7.  Growth-Differentiation Factor 15 Predicts Worsening of Albuminuria in Patients With Type 2 Diabetes 
Diabetes Care  2012;35(11):2340-2346.
Development of micro- or macroalbuminuria is associated with increased risk of cardiorenal complications, particularly in diabetes. For prevention of transition to micro- or macroalbuminuria, more accurate prediction markers on top of classical risk markers are needed. We studied a promising new marker, growth-differentiation factor (GDF)-15, to predict transition to increasing stage of albuminuria in type 2 diabetes mellitus (T2DM). In addition, we looked at the GDF-15 potential in nondiabetic subjects with hypertension (HT).
Case and control subjects were selected from the PREVEND cohort, a large (n = 8,592), prospective general population study on the natural course of albuminuria, with >10 years of follow-up and repeated albuminuria measurements. We found 24 T2DM and 50 HT case subjects transitioning from normo- to macroalbuminuria and 9 T2DM and 25 HT case subjects transitioning from micro- to macroalbuminuria (average follow-up 2.8 years). Control subjects with stable albuminuria were pair matched for age, sex, albuminuria status, and diabetes duration. GDF-15 was measured in samples prior to albuminuria transition.
Prior to transition, GDF-15 was significantly higher in case subjects with T2DM than in control subjects (median [IQR] 1,288 pg/mL [885–1,546] vs. 948 pg/mL [660–1,016], P < 0.001). The odds ratio for transition in albuminuria increased significantly per SD of GDF-15 (2.9 [95% CI 1.1–7.5], P = 0.03). GDF-15 also improved prediction of albuminuria transition, with significant increases in C statistic (from 0.87 to 0.92, P = 0.03) and integrated discrimination improvement (0.148, P = 0.001). In HT, GDF-15 was also independently associated with transition in albuminuria stage (2.0 [1.1–3.5], P = 0.02) and improved prediction significantly.
We identified GDF-15 as a clinically valuable marker for predicting transition in albuminuria stage in T2DM beyond conventional risk markers. These findings were confirmed in nondiabetic HT subjects.
PMCID: PMC3476892  PMID: 22815297
8.  Association between Sodium Intake and Change in Uric Acid, Urine Albumin Excretion, and the Risk of Developing Hypertension 
Circulation  2012;125(25):3108-3116.
In non-hypertensive individuals, a high sodium diet has little acute effect on blood pressure but, for unclear reasons, is associated with hypertension if consumed chronically. We hypothesized that a chronically high sodium intake would be associated with increases in biomarkers of endothelial dysfunction, specifically serum uric acid (SUA) and urine albumin excretion (UAE), and that high sodium intake would be associated with incident hypertension among those with higher SUA and UAE.
Methods and Results
We prospectively analyzed the associations between sodium intake and the change in SUA (N=4062) and UAE (N=4146) among participants of the PREVEND study who were not taking antihypertensive medications. We also examined the association of sodium intake with the incidence of hypertension (N=5556) among non-hypertensive participants. After adjusting for confounders, each 1 gram higher sodium intake was associated with a 1.2µmol/L increase in SUA (p=0.01) and a 4.6mg/d increase in UAE (p<0.001). The relation between sodium intake and incident hypertension varied according to SUA and UAE. For each 1 gram higher sodium intake, the adjusted hazard ratio for developing hypertension was 0.98 (0.89–1.08) among those in the lowest tertile of SUA, and 1.09 (1.02–1.16) among those in the highest. Corresponding hazard ratios were 0.99 (0.93–1.06) among participants whose UAE was <10mg/d, and 1.18 (1.07–1.29) among those whose UAE was >15mg/d.
Over time, higher sodium intake is associated with increases in SUA and UAE. Among individuals with higher SUA and urine UAE, a higher sodium intake is an independent risk factor for developing hypertension.
PMCID: PMC3804910  PMID: 22711274
diet; epidemiology; hypertension; risk factors; sodium
9.  Association of Mild to Moderate Chronic Kidney Disease with Venous Thromboembolism: Pooled Analysis of Five Prospective General Population Cohorts 
Circulation  2012;126(16):1964-1971.
Recent findings suggest that chronic kidney disease (CKD) may be associated with increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.
Methods and Results
We pooled individual participant data from five community-based cohorts from Europe (HUNT2, PREVEND and Tromsø study) and United States (ARIC and CHS study) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria and CKD with objectively verified VTE. To estimate adjusted hazard ratios (HRs) for VTE, categorical and continuous spline models were fit using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1,178 VTE events occurred over 599,453 person-years follow-up. Relative to eGFR 100 mL/min/1.73m2, HRs for VTE were 1.29 (95%CI, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for 60, 1.82 (1.27-2.60) for 45 and 1.95 (1.26-3.01) for 30 mL/min/1.73m2. Compared with albumin-creatinine ratio (ACR) of 5.0 mg/g, the HRs for VTE were 1.34 (1.04-1.72) for 30 mg/g, 1.60 (1.08-2.36) for 300 mg/g and 1.92 (1.19-3.09) for 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted HR for CKD defined as eGFR <60 mL/min/1.73m2 or albuminuria ≥30 mg/g (vs. no CKD) was 1.54 (95%CI, 1.15-2.06). Associations were consistent in subgroups according to age, gender, and comorbidities as well as for unprovoked versus provoked VTE.
Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.
PMCID: PMC3520022  PMID: 22977129
chronic kidney disease; deep vein thrombosis; epidemiology; pulmonary embolism; thromboembolism
10.  Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease 
The New England journal of medicine  2012;367(25):2407-2418.
The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V2-receptor antagonists inhibit cyst growth and slow the decline of kidney function.
In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V2-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.
Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P = 0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P = 0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, −2.61 [mg per milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).
Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 number, NCT00428948.)
PMCID: PMC3760207  PMID: 23121377
11.  Genetic loci influencing kidney function and chronic kidney disease in man 
Chambers, John C | Zhang, Weihua | Lord, Graham M | van der Harst, Pim | Lawlor, Debbie A | Sehmi, Joban S | Gale, Daniel P | Wass, Mark N | Ahmadi, Kourosh R | Bakker, Stephan JL | Beckmann, Jacqui | Bilo, Henk JG | Bochud, Murielle | Brown, Morris J | Caulfield, Mark J | Connell, John M C | Cook, Terence | Cotlarciuc, Ioana | Smith, George Davey | de Silva, Ranil | Deng, Guohong | Devuyst, Olivier | Dikkeschei, Lambert D. | Dimkovic, Nada | Dockrell, Mark | Dominiczak, Anna | Ebrahim, Shah | Eggermann, Thomas | Farrall, Martin | Ferrucci, Luigi | Floege, Jurgen | Forouhi, Nita G | Gansevoort, Ron T | Han, Xijin | Hedblad, Bo | van der Heide, Jaap J Homan | Hepkema, Bouke G | Hernandez-Fuentes, Maria | Hypponen, Elina | Johnson, Toby | de Jong, Paul E | Kleefstra, Nanne | Lagou, Vasiliki | Lapsley, Marta | Li, Yun | Loos, Ruth J F | Luan, Jian'an | Luttropp, Karin | Maréchal, Céline | Melander, Olle | Munroe, Patricia B | Nordfors, Louise | Parsa, Afshin | Penninx, Brenda W. | Perucha, Esperanza | Pouta, Anneli | Prokopenko, Inga | Roderick, Paul J | Ruokonen, Aimo | Samani, Nilesh | Sanna, Serena | Schalling, Martin | Schlessinger, David | Schlieper, Georg | Seelen, Marc AJ | Shuldiner, Alan R | Sjögren, Marketa | Smit, Johannes H. | Snieder, Harold | Soranzo, Nicole | Spector, Timothy D | Stenvinkel, Peter | Sternberg, Michael JE | Swaminathan, Ramasamyiyer | Tanaka, Toshiko | Ubink-Veltmaat, Lielith J. | Uda, Manuela | Vollenweider, Peter | Wallace, Chris | Waterworth, Dawn | Zerres, Klaus | Waeber, Gerard | Wareham, Nicholas J | Maxwell, Patrick H | McCarthy, Mark I | Jarvelin, Marjo-Riitta | Mooser, Vincent | Abecasis, Goncalo R | Lightstone, Liz | Scott, James | Navis, Gerjan | Elliott, Paul | Kooner., Jaspal S
Nature genetics  2010;42(5):373-375.
Chronic kidney disease (CKD), the result of permanent loss of kidney function, is a major global problem. We identify common genetic variants at chr2p12-p13, chr6q26, chr17q23 and chr19q13 associated with serum creatinine, a marker of kidney function (P=10−10 to 10−15). SNPs rs10206899 (near NAT8, chr2p12-p13) and rs4805834 (near SLC7A9, chr19q13) were also associated with CKD. Our findings provide new insight into metabolic, solute and drug-transport pathways underlying susceptibility to CKD.
PMCID: PMC3748585  PMID: 20383145
12.  Rationale and design of the TEMPO ¾ study, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes 
Current management of ADPKD is focused on managing disease complications, not on slowing cyst development or preventing progression to kidney failure. Tolvaptan, a selective vasopressin V2 receptor antagonist, has proven to inhibit kidney cyst growth and preserve kidney function in multiple animal models of polycystic kidney disease. The TEMPO¾ trial will examine the long-term effectiveness and safety of tolvaptan in ADPKD patients.
Study Design
A prospective, three-year, multicenter, double-blind, placebo controlled trial.
Setting & Participants
This trial includes ADPKD patients with a relatively preserved kidney function (baseline eCrCl ≥ 60 mL/min) ≤ 50 years of age and total kidney volume (TKV) measured with magnetic resonance imaging (MRI) ≥ 750 mL
Administration of placebo or tolvaptan, a selective V2 receptor antagonist, dose-titrated to tolerance.
Primary outcome is TKV percent change from baseline for tolvaptan relative to placebo. Secondary outcome parameters include time to ADPKD associated complications (renal function decline, blood pressure control, renal pain and albuminuria) and safety endpoints.
Measurements included TKV, kidney function, albuminuria, kidney pain, adverse events and vital signs.
Between March 2007 and January 2009, 1445 ADPKD patients were enrolled. Preliminary baseline median TKV was 1.46 L and eCrCl was 105 ± 34 mL/min. A pre-specified, blinded, sample size re-calculation at 2/3 enrollment confirmed the likely power of the study to detect 20% differences from placebo in the primary and key secondary endpoints at p<0.05.
This is a preselected ADPKD population chosen for its risk for progression to renal failure and may not represent the general ADPKD population. If the study results are positive with regard to the primary endpoint, confirmation among secondary clinical outcomes will be required.
Results from this randomized clinical trial will show whether treatment with a vasopressin V2 receptor antagonist effectively inhibits cyst growth and disease progression defined as a reduction in change in TKV in ADPKD patients.
Trial registration
PMCID: PMC3725616  PMID: 21333426
clinical trial; ADPKD; polycystic kidney disease; vasopressin
13.  Predictors of Progression in Albuminuria in the General Population: Results from the PREVEND Cohort 
PLoS ONE  2013;8(5):e61119.
Urinary albumin excretion is known to be independently associated with progression of renal and cardiovascular disease. The aim of this study was to identify predictors for progression in albuminuria in the general population.
Data were used of the first 4 screening rounds of a community-based prospective cohort study (PREVEND). Included were 5,825 subjects that at baseline had no known renal disease or macroalbuminuria. Subjects were defined as having progressive albuminuria when they belonged to the quintile of subjects with highest absolute increase in urinary albumin excretion per year and a urinary albumin excretion during the last screening in which they participated of ≥150 mg/24 h. Change in urinary albumin excretion per year was calculated as last available urinary albumin excretion minus baseline UAE divided by follow-up time.
During 9.3 years follow-up 132 subjects had progressive albuminuria. These subjects were significantly older, more often of male gender and had a worse cardiovascular risk profile. In a multivariable model, testing baseline values, significant predictors of progressive albuminuria were male gender (OR 2.23; p<0.001), age (OR 1.03; p<0.001), BMI (OR 1.06; p = 0.02) and baseline albuminuria (OR 5.71; p<0.001). Based on these findings a risk score was made to estimate a subject's risk for progressive albuminuria.
A high baseline albuminuria is by far the most important predictor of progressive albuminuria. Thus, screening for baseline albuminuria will be more important than screening for cardiovascular risk factors in order to identify subjects at risk for progressive albuminuria.
PMCID: PMC3664562  PMID: 23723966
14.  One Risk Assessment Tool for Cardiovascular Disease, Type 2 Diabetes, and Chronic Kidney Disease 
Diabetes Care  2012;35(4):741-748.
Individuals at high risk for chronic cardiometabolic disease (cardiovascular disease [CVD], type 2 diabetes, and chronic kidney disease [CKD]) share many risk factors and would benefit from early intervention. We developed a nonlaboratory-based risk-assessment tool for identification of people at high cardiometabolic disease risk.
Data of three population-based cohorts from different regions of the Netherlands were merged. Participants were 2,840 men and 3,940 women, white, aged 28–85 years, free from CVD, type 2 diabetes, and CKD diagnosis at baseline. The outcome was developing cardiometabolic disease during 7 years follow-up.
Age, BMI, waist circumference, antihypertensive treatment, smoking, family history of myocardial infarction or stroke, and family history of diabetes were significant predictors, whereas former smoking, history of gestational diabetes, and use of lipid-lowering medication were not. The models showed acceptable calibration (Hosmer and Lemeshow statistics, P > 0.05) and discrimination (area under the receiver operating characteristic [ROC] curve 0.82 [95% CI 0.81–0.83] for women and 0.80 [0.78–0.82] for men). Discrimination of individual outcomes was lowest for diabetes (area under the ROC curve 0.70 for men and 0.73 for women) and highest for CVD mortality (0.83 for men and 0.85 for women).
We demonstrate that a single risk stratification tool can identify people at high risk for future CVD, type 2 diabetes, and/or CKD. The present risk-assessment tool can be used for referring the highest risk individuals to health care for further (multivariable) risk assessment and may as such serve as an important part of prevention programs targeting chronic cardiometabolic disease.
PMCID: PMC3308277  PMID: 22338109
15.  Liver Function Tests and Risk Prediction of Incident Type 2 Diabetes: Evaluation in Two Independent Cohorts 
PLoS ONE  2012;7(12):e51496.
Liver function tests might predict the risk of type 2 diabetes. An independent study evaluating utility of these markers compared with an existing prediction model is yet lacking.
Methods and Findings
We performed a case-cohort study, including random subcohort (6.5%) from 38,379 participants with 924 incident diabetes cases (the Dutch contribution to the European Prospective Investigation Into Cancer and Nutrition, EPIC-NL, the Netherlands), and another population-based cohort study including 7,952 participants with 503 incident cases (the Prevention of Renal and Vascular End-stage Disease, PREVEND, Groningen, the Netherlands). We examined predictive value of combination of the Liver function tests (gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase and albumin) above validated models for 7.5-year risk of diabetes (the Cooperative Health Research in the Region of Augsburg, the KORA study). Basic model includes age, sex, BMI, smoking, hypertension and parental diabetes. Clinical models additionally include glucose and uric acid (model1) and HbA1c (model2). In both studies, addition of Liver function tests to the basic model improved the prediction (C-statistic by∼0.020; NRI by∼9.0%; P<0.001). In the EPIC-NL case-cohort study, addition to clinical model1 resulted in statistically significant improvement in the overall population (C-statistic = +0.009; P<0.001; NRI = 8.8%; P<0.001), while addition to clinical model 2 yielded marginal improvement limited to men (C-statistic = +0.007; P = 0.06; NRI = 3.3%; P = 0.04). In the PREVEND cohort study, addition to clinical model 1 resulted in significant improvement in the overall population (C-statistic change = 0.008; P = 0.003; NRI = 3.6%; P = 0.03), with largest improvement in men (C-statistic change = 0.013; P = 0.01; NRI = 5.4%; P = 0.04). In PREVEND, improvement compared to clinical model 2 could not be tested because of lack of HbA1c data.
Liver function tests modestly improve prediction for medium-term risk of incident diabetes above basic and extended clinical prediction models, only if no HbA1c is incorporated. If data on HbA1c are available, Liver function tests have little incremental predictive value, although a small benefit may be present in men.
PMCID: PMC3524238  PMID: 23284703
16.  A Genome-Wide Association Study of Circulating Galectin-3 
PLoS ONE  2012;7(10):e47385.
Galectin-3 is a lectin involved in fibrosis, inflammation and proliferation. Increased circulating levels of galectin-3 have been associated with various diseases, including cancer, immunological disorders, and cardiovascular disease. To enhance our knowledge on galectin-3 biology we performed the first genome-wide association study (GWAS) using the Illumina HumanCytoSNP-12 array imputed with the HapMap 2 CEU panel on plasma galectin-3 levels in 3,776 subjects and follow-up genotyping in an additional 3,516 subjects. We identified 2 genome wide significant loci associated with plasma galectin-3 levels. One locus harbours the LGALS3 gene (rs2274273; P = 2.35×10−188) and the other locus the ABO gene (rs644234; P = 3.65×10−47). The variance explained by the LGALS3 locus was 25.6% and by the ABO locus 3.8% and jointly they explained 29.2%. Rs2274273 lies in high linkage disequilibrium with two non-synonymous SNPs (rs4644; r2 = 1.0, and rs4652; r2 = 0.91) and wet lab follow-up genotyping revealed that both are strongly associated with galectin-3 levels (rs4644; P = 4.97×10−465 and rs4652 P = 1.50×10−421) and were also associated with LGALS3 gene-expression. The origins of our associations should be further validated by means of functional experiments.
PMCID: PMC3467202  PMID: 23056639
17.  Peroxiredoxin 4, A Novel Circulating Biomarker for Oxidative Stress and the Risk of Incident Cardiovascular Disease and All-Cause Mortality 
Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide–degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS).
Methods and Results
We performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD.
Elevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD.
PMCID: PMC3541606  PMID: 23316297
cardiovascular disease; epidemiology; mortality; oxidative stress; peroxiredoxin 4
18.  Indomethacin Reduces Glomerular and Tubular Damage Markers but Not Renal Inflammation in Chronic Kidney Disease Patients: A Post-Hoc Analysis 
PLoS ONE  2012;7(5):e37957.
Under specific conditions non-steroidal anti-inflammatory drugs (NSAIDs) may be used to lower therapy-resistant proteinuria. The potentially beneficial anti-proteinuric, tubulo-protective, and anti-inflammatory effects of NSAIDs may be offset by an increased risk of (renal) side effects. We investigated the effect of indomethacin on urinary markers of glomerular and tubular damage and renal inflammation. We performed a post-hoc analysis of a prospective open-label crossover study in chronic kidney disease patients (n = 12) with mild renal function impairment and stable residual proteinuria of 4.7±4.1 g/d. After a wash-out period of six wks without any RAAS blocking agents or other therapy to lower proteinuria (untreated proteinuria (UP)), patients subsequently received indomethacin 75 mg BID for 4 wks (NSAID). Healthy subjects (n = 10) screened for kidney donation served as controls. Urine and plasma levels of total IgG, IgG4, KIM-1, beta-2-microglobulin, H-FABP, MCP-1 and NGAL were determined using ELISA. Following NSAID treatment, 24 h -urinary excretion of glomerular and proximal tubular damage markers was reduced in comparison with the period without anti-proteinuric treatment (total IgG: UP 131[38–513] vs NSAID 38[17–218] mg/24 h, p<0.01; IgG4: 50[16–68] vs 10[1–38] mg/24 h, p<0.001; beta-2-microglobulin: 200[55–404] vs 50[28–110] ug/24 h, p = 0.03; KIM-1: 9[5]–[14] vs 5[2]–[9] ug/24 h, p = 0.01). Fractional excretions of these damage markers were also reduced by NSAID. The distal tubular marker H-FABP showed a trend to reduction following NSAID treatment. Surprisingly, NSAID treatment did not reduce urinary excretion of the inflammation markers MCP-1 and NGAL, but did reduce plasma MCP-1 levels, resulting in an increased fractional MCP-1 excretion. In conclusion, the anti-proteinuric effect of indomethacin is associated with reduced urinary excretion of glomerular and tubular damage markers, but not with reduced excretion of renal inflammation markers. Future studies should address whether the short term glomerulo- and tubulo-protective effects as observed outweigh the possible side-effects of NSAID treatment on the long term.
PMCID: PMC3360674  PMID: 22662255
19.  Glomerular and Tubular Damage Markers Are Elevated in Patients With Diabetes 
Diabetes Care  2011;34(4):975-981.
We investigated in a cross-sectional study the levels of serum and urinary damage markers in diabetic patients (n = 94) and nondiabetic control subjects (n = 45) to study the association of glomerular (IgG), proximal tubular (kidney injury molecule [KIM]-1, N-acetyl-β-d-glucosaminidase [NAG], neutrophil gelatinase–associated lipocalin [NGAL], and cystatin C), and distal tubular (heart fatty acid–binding protein [H-FABP]) damage markers with kidney disease severity, as assessed by albuminuria and estimated glomerular filtration rate (eGFR).
Damage markers were measured in triplicate in fresh morning urine samples and in plasma.
Of the diabetic patients, 41 were normoalbuminuric, 41 were microalbuminuric, and 12 were macroalbuminuric. Urinary NAG (ninefold), NGAL (1.5-fold), and H-FABP (3.5-fold) were significantly elevated in normoalbuminuric diabetic patients compared with nondiabetic control subjects. Urinary concentrations of all markers increased per albuminuria stratum, except KIM-1. All urinary damage markers, except KIM-1, were significantly associated with albuminuria, independent of age, sex, and plasma concentrations of the corresponding biomarker (standard βs between 0.35 and 0.87; all P ≤ 0.001). All urinary damage markers, except KIM-1, were significantly associated with the eGFR in univariate models (standard βs between −0.38 and −0.21; all P < 0.04). After adjusting for age, sex, plasma concentration of the corresponding damage marker, and albuminuria, only the association of H-FABP with eGFR remained significant (standard β −0.26; P = 0.037).
Glomerular and tubular markers are associated with albuminuria, independently of eGFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage. Only urinary H-FABP is associated with eGFR independently of albuminuria and, therefore, may be a promising urinary damage marker to assess diabetic kidney disease.
PMCID: PMC3064060  PMID: 21307379
20.  The Association of APOE Genotype with Cognitive Function in Persons Aged 35 Years or Older 
PLoS ONE  2011;6(11):e27415.
APOE genotype is associated with the risk of Alzheimer's disease. In the present study, we investigated whether APOE genotype was associated with cognitive function in predominantly middle-aged persons. In a population-based cohort of 4,135 persons aged 35 to 82 years (mean age (SD), 55 (12) years), cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0 points; best score, 175 points). APOE genotype (rs429358 and rs7412) was determined by polymerase chain reaction. The mean RFFT score (SD) of the total cohort was 69 (26) points. Unadjusted, the mean RFFT score in homozygous APOE ε4 carriers was 4.66 points lower than in noncarriers (95% confidence interval, -9.84 to 0.51; p = 0.08). After adjustment for age and other risk factors, the mean RFFT score in homozygous APOE ε4 carriers was 5.24 points lower than in noncarriers (95% confidence interval, -9.41 to -1.07; p = 0.01). The difference in RFFT score was not dependent on age. There was no difference in RFFT score between heterozygous APOE ε4 carriers and noncarriers. The results indicated that homozygous APOE ε4 carriers aged 35 years or older had worse cognitive function than heterozygous carriers and noncarriers.
PMCID: PMC3215744  PMID: 22110642
21.  Reference Data for the Ruff Figural Fluency Test Stratified by Age and Educational Level 
PLoS ONE  2011;6(2):e17045.
The Ruff Figural Fluency Test (RFFT) was developed to avoid the difficulties that were encountered in earlier tests of figural fluency. Although the test characteristics of the RFFT seem to be good and it is a valuable addition to neuropsychological assessments, reference data are still scarce. To this aim, we required 2,404 community dwelling persons in Groningen, the Netherlands to perform the RFFT. All 1,651 persons with a complete RFFT and known educational level formed the reference sample. Their age ranged from 35 to 82 years and their educational level from primary school to university grade. Ninety-six percent of the persons were of Western European descent. All tests were analyzed by two independent examiners and subsequently three measures were calculated: number of unique designs, number of perseverative errors and error ratio. The main finding was that performance on the RFFT was dependent on age and educational level. This was not only observed in older persons but also in young and middle-aged persons. Reference data for the three RFFT measures are presented in groups of five years of age ranging from 35–39 years to 75 years or older.
PMCID: PMC3037396  PMID: 21347325
22.  Age and cystatin C in healthy adults: a collaborative study 
Background. Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum.
Methods. The authors pooled individual-level cross-sectional data from 18 253 persons aged 28–100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.
Results. Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction).
Conclusions. There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.
PMCID: PMC2904248  PMID: 19749145
ageing; chronic kidney disease; cystatin C; epidemiology

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