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Purpose: Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR). Methods: We retrospectively identified patients using olaparib at the Netherlands Cancer Institute – Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012). Results: In total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) μmol/L before/off treatment to 82 (IQR: 20) μmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C–derived eGFR (p = 0.918). Conclusions: This study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C–derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib. [ABSTRACT FROM AUTHOR]

Summary: Early renal dysfunction is associated with a 38% increased fracture risk in individuals aged 65 years and older. In men but not women, early renal dysfunction is associated with decreased femoral neck bone mineral density (BMD) which can be partially explained by increased parathyroid hormone (PTH) concentrations.Introduction: It is uncertain whether early renal dysfunction is associated with osteoporosis and increased fracture risk. The aim of this study was to determine the relationship of decreased renal function with BMD and fracture risk and the role of PTH therein.Methods: We analyzed data of participants aged 65 years and older from the Longitudinal Aging Study Amsterdam. A 6-year fracture follow-up was obtained in 1477 participants. BMD was measured by dual-energy x-ray absorptiometry (n = 535) and vertebral fractures by lateral spinal radiograph (n = 527) in a subsample at baseline. Glomerular filtration rate (eGFR) was estimated according to the modification of diet in renal disease equation and assessed by the five stages of chronic kidney disease (CKD).Results: In men and women, eGFR < 57 ml/min/1.73 m2 (lowest quartile) compared to eGFR > 74 ml/min/1.73 m2 (highest quartile) was associated with a 38% increase in fracture risk after adjustment for relevant confounders [hazard ratio (95%CI): 1.38 (1.17 to 1.61)]. Also, CKD stages 3a and 3b were associated to a 28 and 46% increase in fracture risk, respectively, as compared to CKD stages 1 and 2 together (eGFR > 60 ml/min/1.73 m2) after adjustment for confounders. Renal function was not associated with prevalent vertebral fractures. In men, but not women, lowest quartile of eGFR was related to lower femoral neck BMD as compared to the highest quartile eGFR [unstandardized B (95%CI) − 0.052 g/cm2 (− 0.098 to − 0.006)], after adjustment for relevant confounders. Further adjustment for PTH attenuated this relationship by 27%.Conclusions: In men and women, early decreased renal function (eGFR < 60 ml/min/1.73 m2) was related to increased incident any fracture risk but not with increased prevalence of vertebral fractures. In men, but not women, early renal dysfunction was related to lower femoral neck BMD which could statistically be partially explained by increased PTH concentrations. [ABSTRACT FROM AUTHOR]

Aims: Renal dysfunction is a risk factor for cardiovascular disease, including atrial fibrillation (AF) and mortality. However, the exact pathobiology linking different renal dysfunction measures, such as albumin excretion or glomerular filtration rate (GFR), to cardiovascular- and AF risk are unclear. In this study, we investigated the association of several renal function measures and incident AF, and whether the relation between renal measures and outcomes is modified by AF.Methods and Results: We examined 8265 individuals (age 49 ± 13 years, 50% women) included in the PREVEND study. We used albumin excretion (morning void and 24-h urine samples), serum creatinine, cystatin C, and Cystatin C-based, creatinine-based, and creatinine-cystatin C-based GFR as renal function measures; results: During a follow-up of 9.8 ± 2.3 years, 267 participants (3.2%) developed AF. In the multivariate-adjusted model, GFR, estimated by creatinine, cystatin C, or the combination was not associated with incident AF. However, increased albumin excretion was strongly associated with incident AF; urine albumin concentration and excretion (HRmorning void 1.10, P = 0.005 and HR24-hr collection 1.05, P = 0.033) and albumin creatinine ratio (HRmorning void 1.05, P = 0.010 and HR24-hr collection 1.06, P < 0.001). Interaction terms of incident AF and renal measures were not significant for incident cerebrovascular events, peripheral vascular events, ischemic heart disease, heart failure, and mortality.Conclusion: In this community-based cohort, increased albumin excretion, and not GFR, was associated with incident AF, independent of established cardiovascular risk factors. Incidence of AF did not largely alter the association of renal dysfunction and cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Summary: We studied the relation between a diet that is high in acid-forming nutrients (e.g. proteins) and low in base-forming nutrients (e.g. potassium) and bone structure. We showed a negative relation, which was more prominent if proteins were of animal rather than of vegetable origin and if intake of dietary fibre was high. Introduction: Studies on dietary acid load (DAL) and fractures have shown inconsistent results. Associations between DAL, bone mineral density (BMD) and trabecular bone integrity might play a role in these inconsistencies and might be influenced by renal function and dietary fibre intake. Therefore, our aim was to study (1) associations of DAL with BMD and with the trabecular bone score (TBS) and (2) the potential influence of renal function and dietary fibre in these associations. Methods: Dutch individuals aged 45 years and over ( n = 4672) participating in the prospective cohort of the Rotterdam study were included. Based on food frequency questionnaires, three indices of DAL were calculated: the net endogenous acid production (NEAP) and the ratios of vegetable or animal protein and potassium (VegPro/K and AnPro/K). Data on lumbar spinal TBS and BMD were derived from dual-energy X-ray absorptiometry measurements. Results: Independent of confounders, NEAP and AnPro/K, but not VegPro/K, were associated with low TBS (standardized β (95%) = −0.04 (−0.07, −0.01) and −0.08 (−0.11, −0.04)) but not with BMD. Associations of AnPro/K and VegPro/K with TBS were non-linear and differently shaped. Unfavourable associations between NEAP, BMD and TBS were mainly present in subgroups with high fibre intake. Conclusions: High NEAP was associated with low TBS. Associations of AnPro/K and VegPro/K and TBS were non-linear and differently shaped. No significant associations of DAL with BMD were observed, nor was there any significant interaction between DAL and renal function. Mainly in participants with high intake of dietary fibre, DAL might be detrimental to bone. [ABSTRACT FROM AUTHOR]

Background: Evidence has suggested that protein from dairy may be less detrimental to renal health than protein from nondairy products. However, to our knowledge, no previous studies have used cystatin C-based measures of the estimated glomerular filtration rate (eGFR). Objective: We investigated the associations of sources of protein and dairy with the change in the eGFR in persons with a normal or mildly decreased eGFR. Design: We included 3798 participants, aged 26-65 y, from the Doetinchem Cohort study who were examined ≥3 times 5 y apart. Intakes of protein and dairy and subtypes of protein and dairy were assessed at each round. With the use of the Chronic Kidney Disease Epidemiology Collaboration equation, the eGFR was estimated from cystatin C with all available samples per participant examined in one assay run. Generalized estimating equation models, which were adjusted for lifestyle, biological, and other dietary factors (monounsaturated fat, polyunsaturated fat, phosphorus, magnesium, calcium, and vitamin D) were performed. Results: The mean baseline eGFR in the total cohort and in subjects with a mildly decreased eGFR (≥1 eGFR of 60-90 mL ⋅ min-1 ⋅ 1.73 m-2 during follow-up; n = 1326) was 108.6 and 95.2 mL ⋅ min-1 ⋅ 1.73 m-2, and the mean annual decline in both groups was 1.01 and 1.34 mL ⋅ min-1 ⋅ 1.73 m-2, respectively. Intakes of total, vegetable, animal, and nondairy protein, dairy protein, cheese, total dairy, high-fat dairy, and fermented dairy were not associated with eGFR changes. In individuals with a mildly decreased eGFR, higher consumption of milk, milk products, and low-fat dairy was associated with less annual decline in the eGFR (P-trend = 0.003). These associations were partially explained by dietary components of dairy (monounsaturated fat, polyunsaturated fat, phosphorus, magnesium, calcium, and vitamin D; P-trend < 0.04). Conclusions: Higher low-fat dairy consumption, but not sources of protein, is associated with less annual decline in the eGFR, particularly in individuals with a mildly decreased eGFR. These associations are partly attributable to other major components of dairy. Confirmation of these results will improve our ability to understand the role of dairy consumption in the prevention of renal dysfunction. [ABSTRACT FROM AUTHOR]

Objective: To describe influences on decision-making and prognostic variables in the prenatal management of fetal lower urinary tract obstruction (LUTO).Methods: This was a prospective registry study of pregnant women with a male fetus with LUTO from centers within the British Isles and The Netherlands. Women and/or their clinicians were given the treatment option of either conservative management or vesicoamniotic shunting (VAS). Baseline characteristics of women in the registry, reasons for entry to the registry and pregnancy outcomes were assessed. The main study outcomes were survival to 28 days after delivery, further survival to 2 years and renal function. Logistic regression analysis was used to examine prognostic variables that affected outcome. Results were compared with those of women in a randomized controlled trial (RCT) who were allocated randomly to a treatment option.Results: Forty-five women were registered, of whom 78% (35/45) underwent conservative management. Twenty-seven women entered the registry owing to their clinician's preference for management and 18 because of their own preference. Compared to the conservative-management group of the RCT, a higher proportion of women in the registry opting for conservative management had a normal amniotic fluid volume at diagnosis (P = 0.05) and a diagnosis of LUTO ≥ 24 weeks' gestation (P = 0.003). On multivariable logistic regression analysis, these variables showed a significant association with perinatal survival (P < 0.001). Survival to 28 days after delivery was higher in the conservative-management group, at 69% (24/35), compared to 40% (4/10) in the VAS group (P = 0.02) but this difference had limited statistical significance owing to small study size (relative risk, 0.58 (95% CI, 0.26-1.29); P = 0.14).Conclusion: In our prospective registry, the majority of fetuses with LUTO received conservative management, which was associated with better short- and long-term outcomes. A significant proportion of these pregnancies had normal amniotic fluid volume and a gestational age at diagnosis of ≥ 24 weeks, characteristics shown to be associated with improved survival. [ABSTRACT FROM AUTHOR]

Background: the impact of renal function and its changes and the occurrence of cardiovascular events on changes in N-terminal pro-brain natriuretic peptide levels (NT-proBNP) is unknown in very old age. Objective: to assess whether increase in NT-proBNP levels over time is still associated with cardiac disease and mortality in very old age, independent of renal function. Methods: changes in NT-proBNP levels between age 85 and 90 years and their associations with incident cardiac disease, (cardiovascular) mortality and renal function were assessed in 252 nonagenarian participants from a population-based sample of the Leiden 85-plus Study. Results: median NT-proBNP increase over 5 years was 154 pg/ml (inter-quartile range: 29-549), while in the same period estimated glomerular filtration rate (eGFR) decreased by 5.8 ml/min/1.73 m2 (standard deviation 7.5). Participants with increasing NT-proBNP levels more frequently developed heart failure and atrial fibrillation (odds ratio 2.79, 95% confidence interval (CI) 1.11-7.02 and 2.63, 95% CI 1.02-6.79, respectively, adjusted for eGFR at age 85 and change in eGFR) between age 85 and 90 years. Increasing NT-proBNP levels between age 85 and 90 years were associated with an increased cardiovascular mortality risk after age 90 years compared with not-increasing NT-proBNP levels (hazard ratio 1.62, 95% CI 1.04-2.51, adjusted for eGFR at age 90 years and change in eGFR). Conclusion: in the oldest old, increase in NT-proBNP is associated with incident heart failure and atrial fibrillation and risk for cardiovascular mortality, independent of decreasing renal function. [ABSTRACT FROM AUTHOR]

Background: arterial stiffening is a marker of vascular ageing and an independent risk factor for cardiovascular disease. A potential mechanism linking cardiovascular disease to chronic kidney disease might be the change in arterial elasticity. We aim to determine the association between renal function and arterial stiffness in older subjects.Design: cross-sectional study.Setting: Rotterdam study, a population-based cohort study.Subjects: we included 3,279 subjects from 1997 to 1999 with a mean age of 71.9 years.Methods: estimation of glomerular filtration rate (eGFR) was used to assess renal function. Aortic pulse wave velocity (PWV) and carotid distensibility coefficient were used as measures of arterial stiffness.Results: each standard deviation increase in eGFR, adjusting for age and sex, was associated with 0.14 m/s lower PWV [95% confidence interval (CI): −0.23, −0.05]. Further adjustments for socio-demographic and cardiovascular risk factors did not change the association (β: −0.16 m/s; 95% CI: −0.26, −0.06). There was a linear association between mean values of PWV and quartiles of glomerular filtration rate (P for trend = 0.006). There was no association between decreased renal function and carotid distensibility. There was no statistical difference in the strength of the association between renal function and PWV in subgroups of participants with and without cardiovascular risk factors.Conclusions: in this large population-based study of elderly subjects, our findings suggest that renal impairment is associated with aortic stiffness. This association is independent of cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Objective: to investigate the association between a decreased estimated glomerular filtration rate (eGFR), albuminuria and mortality in elderly patients with type 2 diabetes mellitus (T2DM).Design: prospective observational cohort study.Setting: primary care.Subjects: eight hundred and ten patients, ≥65 years with T2DM. Analyses were performed in age strata: 65–75 (n = 471), >75 (n = 339) years.Methods: Cox proportional hazard modelling was used to investigate the association between eGFR, albuminuria and all-cause and cardiovascular mortality after a median follow-up of 9.8 years.Results: an eGFR <45 and 45–60 ml/min/1.73 m2 is associated with increased cardiovascular mortality in patients of 65–75 years, hazard ratio (HR): 3.29 (1.58–6.86) and 1.78 (1.09–2.90), respectively; in those >75 years increased cardiovascular mortality was observed when eGFR was <45 ml/min/1.73 m2: 2.42 (1.47–3.69). Compared with patients of 65–75 years, an eGFR >60 ml/min/1.73 m2 and normo-albuminuria, fully adjusted HRs for cardiovascular mortality were 2.26 (1.04–4.92) and 4.86 (2.33–10.15) for those aged 65–75 years, an eGFR of 45–60 ml/min/1.73 m2 and normo-albuminuria or albuminuria, respectively; HRs were 1.33 (0.67–2.66) and 2.01 (1.02–3.94), respectively, for those >75 years.Conclusions: an eGFR of 45–60 ml/min/1.73 m2 in T2DM patients is associated with increased mortality in patients aged 65–75 years but not in those >75 years. Albuminuria is associated with increased mortality in patients >65 years. [ABSTRACT FROM AUTHOR]

There is increasing evidence for a role of genetic predisposition in the etiology of kidney disease, but linkage scans have been poorly replicated. Here we performed a genome-wide linkage analysis of serum creatinine on 2859 individuals from isolated villages in South Tyrol (Italy), Rucphen (The Netherlands) and Vis Island (Croatia), populations that have been stable and permanently resident in their region. Linkage of serum creatinine levels to loci on chromosomes 7p14, 9p21, 11p15, 15q15-21, 16p13, and 18p11 was successfully replicated in at least one discovery population or in the pooled analysis. A novel locus was found on chromosome 10p11. Linkage to chromosome 22q13, independent of diabetes and hypertension, was detected over a region containing the non-muscle myosin heavy chain type II isoform A (MYH9) gene (LOD score=3.52). In non-diabetic individuals, serum creatinine was associated with this gene in two of the three populations and in meta-analysis (SNP rs11089788, P-value=0.0089). In populations sharing a homogeneous environment and genetic background, heritability of serum creatinine was higher than in outbred populations, with consequent detection of a larger number of loci than reported before. Our finding of a replicated association of serum creatinine with the MYH9 gene, recently linked to pathological renal conditions in African Americans, suggests that this gene may also influence kidney function in healthy Europeans.Kidney International (2009) 76, 297–306; doi:10.1038/ki.2009.135; published online 22 April 2009 [ABSTRACT FROM AUTHOR]

Objectives: We sought to investigate the relationship between increased central venous pressure (CVP), renal function, and mortality in a broad spectrum of cardiovascular patients. Background: The pathophysiology of impaired renal function in cardiovascular disease is multifactorial. The relative importance of increased CVP has not been addressed previously. Methods: A total of 2,557 patients who underwent right heart catheterization in the University Medical Center Groningen, the Netherlands, between January 1, 1989, and December 31, 2006, were identified, and their data were extracted from electronic databases. Estimated glomerular filtration rate (eGFR) was assessed with the simplified modification of diet in renal disease formula. Results: Mean age was 59 ± 15 years, and 57% were men. Mean eGFR was 65 ± 24 ml/min/1.73 m2, with a cardiac index of 2.9 ± 0.8 l/min/m2 and CVP of 5.9 ± 4.3 mm Hg. We found that CVP was associated with cardiac index (r = −0.259, p < 0.0001) and eGFR (r = −0.147, p < 0.0001). Also, cardiac index was associated with eGFR (r = 0.123, p < 0.0001). In multivariate analysis CVP remained associated with eGFR (r = −0.108, p < 0.0001). In a median follow-up time of 10.7 years, 741 (29%) patients died. We found that CVP was an independent predictor of reduced survival (hazard ratio: 1.03 per mm Hg increase, 95% confidence interval: 1.01 to 1.05, p = 0.0032). Conclusions: Increased CVP is associated with impaired renal function and independently related to all-cause mortality in a broad spectrum of patients with cardiovascular disease. [Copyright &y& Elsevier]

Background Options for the treatment of infections caused by resistant gram-positive bacteria are limited in children with kidney disease. Ceftaroline (CFD) may be an attractive option but dosing recommendations are not available for children with renal dysfunction. We present a case of pharmacokinetics (PK) model-based individualization of CFD in an infant with kidney disease and mediastinitis. A 5-week-old infant with a hypoplastic left side of the heart developed mediastinitis following a Norwood and BT shunt. Blood and chest washout cultures grew S. epidermidis. Vancomycin therapy led to acute kidney injury (AKI) (eGFR ~15mL/minute) and therefore, CFD was initiated at 8 mg/kg every 12 hours. The model-based clinical service was consulted to assist with dosing. Methods Plasma levels were drawn on day 2 and 10 of CFD. CFD concentrations were determined by HPLC. The pharmacodynamic (PD) target used the MIC of the isolate, 1 µg/mL, and assumed drug diffusion into the mediastinum at 20% of plasma. The PD target was ƒT>MIC at 100%. Individual PK parameters were estimated using Bayesian estimation with MWPharm++ (Mediware, the Netherlands). Results CFD dosing of 8 mg/kg every 12 hours resulted in concentrations well above the target. The trough level was 10 times higher than levels seen in clinical trials. Repeat levels were checked on day 10 due to improved renal function (eGFR 30 mL/minute) and changes in volume status. Changes in both clearance and volume were noted. ƒT>MIC was maintained 100% during dosing intervals. We dose optimized CFD to achieve the target while minimizing potential toxicity with long-term use. A new dosing regimen, 5.4 mg/kg every 8 hours, was started on day 12 and continued for 6 weeks. Conclusion This is the first case report of CFD use in a child with AKI. Though initial dosing resulted in high concentrations, no adverse effects were noted. Successful treatment was completed with a final dosing regimen of 5.3 mg/kg every 8 hours, below the recommended 8 mg/kg every 8 hours. Lower dosing was needed to decrease high drug exposure due to the decreased clearance. This case also demonstrated the feasibility of PK model-based precision dosing within 48 hours, and documented utility in the setting of changes in renal function. Further PK/PD studies are needed in children with renal dysfunction. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Essentials The association between chronic kidney disease and bleeding is unknown. We followed 10 347 subjects at high cardiovascular risk for bleeding events. Chronic kidney disease was associated with a 1.5-fold increased bleeding risk. Especially albuminuria rather than decreased kidney function was associated with bleeding events., Summary: Background There are indications that patients with chronic kidney disease have an increased bleeding risk. Objectives To investigate the association between chronic kidney disease and bleeding in patients at high cardiovascular risk. Methods We included 10 347 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2015 for an outpatient visit with classic risk factors for arterial disease or with symptomatic arterial disease (Second Manifestation of Arterial disease [SMART] cohort). Patients were staged according to the KDIGO guidelines, on the basis of estimated glomerular filtration rate (eGFR) and albuminuria, and were followed for the occurrence of major hemorrhagic events until March 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding were calculated with Cox proportional hazards analyses. Results The incidence rate for bleeding in subjects with chronic kidney disease was 8.0 per 1000 person-years and that for subjects without chronic kidney disease was 3.5 per 1000 person-years. Patients with chronic kidney disease (n = 2443) had a 1.5-fold (95% CI 1.2-1.9) increased risk of bleeding as compared with subjects without chronic kidney disease (n = 7904) after adjustment. Subjects with an eGFR of < 45 mL min -1  1.73 m -2 with albuminuria had a 3.5-fold (95% CI 2.3-5.3) increased bleeding risk, whereas an eGFR of < 45 mL min -1  1.73 m -2 without albuminuria was not associated with an increased bleeding risk (HR 1.3, 95% CI 0.7-2.5). Conclusion Chronic kidney disease is a risk factor for bleeding in patients with classic risk factors for arterial disease or with symptomatic arterial disease, especially in the presence of albuminuria., (© 2017 University Medical Center Utrecht. Journal of Thrombosis and Haemostasis © 2017 International Society on Thrombosis and Haemostasis.)

Background: Chronic kidney disease (CKD) is an important comorbidity during human immunodeficiency virus (HIV) infection. Historically, HIV-associated nephropathy has been the predominant cause of CKD and has primarily been observed in people of African ancestry. This study aims to investigate the role of ethnicity in relation to CKD risk in recent years., Methods: Analyses were performed including 16 836 patients from the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. Baseline was defined as the first available creatinine level measurement after 1 January 2007; CKD was defined as a glomerular filtration rate of <60 mL/min/1.73 m(2). The associations between ethnicity and both prevalent CKD at baseline and incident CKD during follow-up were analyzed., Results: The prevalence of baseline CKD was 2.7% (460 of 16 836 patients). Birth in a sub-Saharan African country (hereafter, "SSA origin") was significantly associated with baseline CKD (adjusted odds ratio 1.49; 95% confidence interval [CI], 1.04-2.13). During follow-up (median duration, 4.7 years; interquartile range, 2.4-5.2), the rate of incident CKD was 6.0 events per 1000 person-years. The risk of newly developing CKD was similar between patients of SSA origin and those born in Western Europe, Australia, or New Zealand (adjusted hazard ratio, 1.00; 95% CI, .63-1.59)., Conclusions: Among HIV-infected patients in the Netherlands, being of SSA origin was associated with a higher baseline CKD prevalence but had no impact on newly developing CKD over time. This suggests a shift in the etiology of CKD from HIV-associated nephropathy toward other etiologies., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)