Effect of absolute blood volume measurement-guided fluid management on the incidence of intradialytic hypotension-associated events: a randomised controlled trial.

Background: Ultrafiltration to target weight during haemodialysis is complicated by intradialytic hypotension-associated adverse events (IHAAEs) in 10-30% of dialysis treatments. IHAAEs are caused by critical reductions in absolute blood volume (ABV), due to the interaction of ultrafiltration, refill and compensatory mechanisms. Non-randomised studies have suggested that ABV-guided treatment, using an indicator dilution technique employing the blood volume monitor on the dialysis machine, could reduce the incidence of IHAAEs. Methods: We performed an open-label randomised controlled trial. Patients were randomly assigned to adjustment of target weight guided by ABV measurements or standard care. The primary outcome was the change in the incidence of IHAAEs from baseline, defined as the percentage of treatment episodes in a 4-week period where the patient had a systolic blood pressure <90 mmHg or symptoms of impending hypotension. ABV measurements were compared with anthropomorphometric estimation and the gold standard using isotope dilution. Results: A total of 56 patients were randomised, of whom 29 were allocated to ABV-guided treatment and 27 to standard care. Overall baseline incidence of IHAAEs was 26.0%. ABV-guided treatment significantly reduced the incidence of IHAAEs compared with standard care, with a mean change from baseline of -9.6% [95% confidence interval (CI) -17.3 to -1.8) versus 2.4% (95% CI -2.3-7.2). The adjusted difference between the groups was 10.5% (95% CI 1.3-19.8; P = .026). ABV measurement had moderate agreement with other methods to estimate blood volume. The sensitivity for the previously suggested threshold of a post-dialysis normalised blood volume of 65 ml/kg was observed to be 74% in this study. Conclusions: ABV-guided volume management significantly reduced IHAAEs compared with standard care. The clinical relevance of the previously suggested threshold of 65 ml/kg cannot be firmly concluded on the basis of our results. If confirmed in a larger trial, this intervention could potentially change dialysis practice and impact patient care in a clinically meaningful way.

Appraising prediction research: a guide and meta-review on bias and applicability assessment using the Prediction model Risk Of Bias ASsessment Tool (PROBAST).

Over the past few years, a large number of prediction models have been published, often of poor methodological quality. Seemingly objective and straightforward, prediction models provide a risk estimate for the outcome of interest, usually based on readily available clinical information. Yet, using models of substandard methodological rigour, especially without external validation, may result in incorrect risk estimates and consequently misclassification. To assess and combat bias in prediction research the prediction model risk of bias assessment tool (PROBAST) was published in 2019. This risk of bias (ROB) tool includes four domains and 20 signalling questions highlighting methodological flaws, and provides guidance in assessing the applicability of the model. In this paper, the PROBAST will be discussed, along with an in-depth review of two commonly encountered pitfalls in prediction modelling that may induce bias: overfitting and composite endpoints. We illustrate the prevalence of potential bias in prediction models with a meta-review of 50 systematic reviews that used the PROBAST to appraise their included studies, thus including 1510 different studies on 2104 prediction models. All domains showed an unclear or high ROB; these results were markedly stable over time, highlighting the urgent need for attention on bias in prediction research. This article aims to do just that by providing (1) the clinician with tools to evaluate the (methodological) quality of a clinical prediction model, (2) the researcher working on a review with methods to appraise the included models, and (3) the researcher developing a model with suggestions to improve model quality.

Quality of life of children with hearing loss in special and mainstream education: A longitudinal study.

OBJECTIVES: To compare the quality of life (QoL) of children with hearing loss (HL) and children with normal hearing (NH) and to examine how the QoL of children with HL changes over time, considering language skills, type of hearing device, degree of HL, and type of education. METHODS AND MATERIALS: This longitudinal study included 62 children with HL and their parents. Developmental outcome data were collected at two time points, when the mean ages of the children were 4 and 11 years. The Pediatric Quality of Life (PedsQL™) questionnaire, which includes assessments of Physical, Emotional, Social, and School functioning, was completed by parents at both time points and by the children with HL at the second time point. Receptive and expressive language skills at 4 years were assessed by the Reynell Developmental Language Scale. Results were compared with a Dutch normative sample. RESULTS: The QoL of children with HL was similar to that of children with NH at both time points on two of the four QoL scales, Emotional and Physical functioning. On the other two scales, Social and School functioning, children with HL who attended special education and children who switched to mainstream education showed lower scores than children with HL who were consistently in mainstream education and lower scores than children with NH. The School QoL of children with HL decreased over time, as did the School QoL of children with NH. Social QoL of children with cochlear implants decreased over time, but this was not the case in children with hearing aids. Language skills and the degree of HL did not clinically improve the QoL over time of preschool children with HL. CONCLUSIONS: The QoL of children with HL in mainstream education and the Physical and Emotional QoL of all children with HL were satisfactory. It is essential to develop specific guidance regarding school activities for children with HL in special education and for children with HL who switch to mainstream education in order to increase their social QoL.

The (cost) effectiveness of guided internet-based self-help CBT for dialysis patients with symptoms of depression: study protocol of a randomised controlled trial.

BACKGROUND: Only a minority of dialysis patients with depressive symptoms are diagnosed and receive treatment. Depressive symptoms are highly prevalent in this population and are associated with adverse clinical outcomes. Underlying factors for this undertreatment may be the lack of evidence for the safety and effectivity of antidepressant medication, the reluctance of patients to adhere to antidepressant medication, the lack of mental healthcare provision in somatic healthcare environments and end-stage renal disease (ESRD) related physical limitations that complicate face-to-face psychotherapy. Guided Internet-based self-help treatment has demonstrated to be effective for depressive symptoms in other chronic patient populations and may overcome these barriers. The aim of this study is to investigate the (cost) effectiveness of a guided Internet-based self-help intervention for symptoms of depression in dialysis patients. METHODS: This study is a cluster randomized controlled trial (RCT) that investigates the effectiveness of a 5-week Internet-based self-help Problem Solving Therapy (PST) for depressive symptoms in dialysis patients. Depressive symptoms will be measured using the Beck Depression Inventory - second edition (BDI-II), with a cut-off score of ≥10. We aim to include 206 dialysis patients with depressive symptoms who will be cluster randomized to the intervention or the Care as Usual (CAU) control group. Secondary outcomes will include anxiety symptoms, quality of life, economic costs and clinical outcomes, such as inflammatory factors and hair cortisol levels. Assessments will take place at baseline (T0), 2 weeks after intervention (T1) and 6 months (T2), 12 months (T3) and 18 months (T4) after intervention. The control group will be measured at the same time points. Analysis will be based on the intention-to-treat principle. Mixed models will be used to assess the changes within each condition between pre-treatment and post-treatment. DISCUSSION: If demonstrated to be (cost) effective, Internet-based PST will offer new possibilities to treat dialysis patients with depressive symptoms and to improve their quality of care. TRIAL REGISTRATION: Dutch Trial Register: Trial NL6648 (NTR6834) (prospectively registered 13th November 2017).

Patient-reported outcome measures: selection of a valid questionnaire for routine symptom assessment in patients with advanced chronic kidney disease - a four-phase mixed methods study.

BACKGROUND: Patient-reported outcome measures (PROMs) are becoming increasingly important in healthcare. In nephrology, there is no agreement on which chronic kidney disease (CKD) symptom questionnaire to use. Therefore, the aim of this study is to select a valid symptom questionnaire for routine assessment in patients with advanced CKD. METHODS: A four-phase mixed methods approach, using qualitative and quantitative research methods, was applied. First, a systematic literature search was conducted to retrieve existing symptom questionnaires. Second, a symptom list was created including all symptoms in existing questionnaires and symptoms mentioned in interviews with patients with CKD, from which symptom clusters were identified. Next, questionnaires were selected based on predefined criteria regarding content validity. Last, two online feedback panels of patients with CKD (n = 151) and experts (n = 6) reviewed the most promising questionnaires. RESULTS: The literature search identified 121 questionnaires, of which 28 were potentially suitable for symptom assessment in patients with advanced CKD. 101 unique symptoms and 10 symptom clusters were distinguished. Based on predefined criteria, the Dialysis Symptom Index (DSI) and Palliative Care Outcome Scale-Renal Version (IPOS-Renal) were selected and reviewed by feedback panels. Patients needed 5.4 and 7.5 min to complete the DSI and IPOS-Renal, respectively (p < 0.001). Patients experienced the DSI as more specific, complete and straightforward compared to the IPOS-Renal. CONCLUSIONS: The DSI was found to be valid and reliable, the most relevant, complete, and comprehensible symptom questionnaire available for routine assessment in patients with advanced CKD. Routine PROMs collection could be of great value to healthcare, both at individual patient and national level. Feedback on scores and involvement of healthcare providers may promote adaptation and implementation in healthcare.

Ethnic Differences in the Association of Depressive Symptoms with Clinical Outcome in Dialysis Patients.

BACKGROUND: Studies show mixed results on the association between depressive symptoms and adverse clinical outcomes in patients on dialysis therapy. Ethnicity may play a role in these heterogeneous results. No studies have investigated the interplay between ethnicity and depressive symptoms on clinical outcome in this patient population. This study aims to examine interaction between ethnicity and depressive symptoms on hospitalization and mortality in dialysis patients. METHODS: A multi-ethnic cohort in 10 dialysis centers included 687 dialysis patients between 2012 and 2017, with an average follow-up of 3.2 years. Depressive symptoms were measured using the Beck Depression Inventory. Interaction was assessed by investigating excess risk on an additive scale using both absolute rates and relative risks. Multivariable regression models included demographic, social, and clinical variables. RESULTS: Adverse outcomes are more pronounced in native patients, compared to immigrant patients. The risk for mortality and hospitalization is considerably higher in native patients compared to immigrants. An excess risk on an additive scale indicates the presence of possible causal interaction. CONCLUSIONS: Depressive symptoms are a risk factor for hospitalization and mortality, especially in native dialysis patients. Adverse clinical events associated with depressive symptoms differ among ethnic groups. This differential association could play a role in the conflicting findings in literature. Ethnicity is an important factor when investigating depressive symptoms and clinical outcome in dialysis patients. Future research should focus on the possible mechanisms and pathways involved in these differential associations.

Prevalence and Risk of Protein-Energy Wasting Assessed by Subjective Global Assessment in Older Adults With Advanced Chronic Kidney Disease: Results From the EQUAL Study.

OBJECTIVES: Prevalence and risk factors for protein-energy wasting (PEW) are poorly studied in the nondialysis, older population with advanced chronic kidney disease (CKD). Our aim was to evaluate the prevalence of PEW in advanced stage CKD patients aged greater than 65 years. Furthermore, we aimed to describe risk factors for PEW in the overall study population and among obese individuals. DESIGN: Prospective observational cohort study. METHODS: The EQUAL study, a European Quality Study on treatment in advanced chronic kidney disease, is a multicenter prospective observational cohort study in six European countries. We included patients aged ≥65 years with incident glomerular filtration rate <20mL/min/1.73m2 not on dialysis attending nephrology care. PEW was assessed by 7-point Subjective Global Assessment (7-p SGA). RESULTS: In general, the study cohort (n = 1,334) was overweight (mean body mass index [BMI] 28.4 kg/m2). The majority of the patients had a normal nutritional status (SGA 6-7), 26% had moderate PEW (SGA 3-5), and less than 1% had severe PEW (SGA 1-2). Muscle wasting and loss of fat tissue were the most frequent alterations according to the SGA subscales, especially in those aged >80 years. The prevalence of PEW was higher among women, increased with age, and was higher in those with depression/dementia. PEW was the most common in those with underweight (BMI <22 kg/m2), 55% or normal weight (BMI 22-25 kg/m2), 40%. In obese individuals (BMI >30 kg/m2), 25% were diagnosed with protein wasting. Risk factors for SGA ≤5 in obese people were similar to those for the overall study population. CONCLUSION: This European multicenter study shows that the prevalence of PEW is high in patients with advanced CKD aged >65 years. The risk of PEW increases substantially with age and is commonly characterized by muscle wasting. Our study suggests that focus on nutrition should start early in the follow-up of older adults with CKD.

Short-Form 12 or Short-Form 36 to measure quality-of-life changes in dialysis patients?

BACKGROUND: Short-Form 36 (SF-36) is a self-report health-related quality-of-life (HRQOL) questionnaire, widely used in dialysis patients. It consists of physical and mental component scores (PCS/MCS), ranging from 0 to 100. To improve efficiency, the Short-Form 12 (SF-12) was developed to reproduce PCS and MCS. We assessed the ability of SF-12 versus SF-36 to detect change over time, and the association of SF-12 versus SF-36 with short-term and long-term mortality in dialysis patients. METHODS: Patients were selected from the Netherlands Cooperative Study on the Adequacy of Dialysis (N = 1379), a prospective follow-up study among incident dialysis patients (62.1% HD) who completed SF-36 measurements every 6 months. Changes in scores of SF-12 versus SF-36 were compared with intra-class correlation coefficients (ICCs). Subsequently, Bland-Altman plots were used to assess limits of agreement. Relationship with mortality was assessed with Cox models with and without a time-dependent variable, adjusted for age, sex, ethnicity, comorbidity and dialysis modality at baseline. RESULTS: ICC for change in scores was 0.90 for MCS and 0.84 for PCS. Mean difference was -0.1 and 0.2, respectively, and limits of agreement were -8.3 to 8.4 for MCS change in scores and -8.8 to 9.2 for PCS. Adjusted hazard ratio's for mortality per 5 units increment were 0.87 (95% CI: 0.84-0.91) for MCS12, 0.87 (95% CI: 0.84-0.90) for MCS36, 0.79 (95% CI: 0.76-0.83) for PCS12 and 0.75 (95% CI: 0.71-0.78) for PCS36. CONCLUSIONS: SF-12 can be used to detect change in HRQOL in cohort studies on dialysis patients. SF-12 and SF-36 were similarly associated with short-term and long-term mortality. However, the wide limits of agreement indicate that SF-12 and SF-36 can give different scores on the individual level, suggesting that for individual purposes SF-36 instead of SF-12 should be used.

Differences in progression to ESRD between black and white patients receiving predialysis care in a universal health care system.

BACKGROUND AND OBJECTIVES: Studies performed in the United States showed that blacks progress from CKD to ESRD faster than do whites. Possible explanations are differences in health care system factors. This study investigated whether progression is also faster in a universal health care system, where all patients receive comparable care. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the PREdialysis PAtient REcord study, a multicenter follow-up study of patients with CKD who started predialysis care in The Netherlands (1999-2011), were analyzed. Time-dependent Cox proportional hazards models were used to estimate the hazard ratio (HR) for starting renal replacement therapy (RRT), and linear mixed models were used to compare renal function decline (RFD) between blacks and whites. To explore possible mechanisms, analyses were adjusted for patient characteristics. RESULTS: At initiation of predialysis care, blacks (n=49) were younger and had more diabetes mellitus, higher proteinuria levels, and a higher estimated GFR than whites (n=946). Median follow-up time in months was similar (blacks: 13.9 [boundaries of interquartile range (IQR), 5.3 to 19.5]; whites: 13.1 [IQR, 5.1 to 24.0]). For blacks compared with whites, the crude HR for starting RRT within the first 15 months was 0.86 (95% confidence interval [CI], 0.55 to 1.34) and from 15 months onward, 1.93 (95% CI, 1.02 to 3.68), which increased after adjustment. RFD was faster by 0.18 (95% CI, 0.05 to 0.32) ml/min per 1.73 m(2) per month in blacks compared with whites. CONCLUSION: Blacks receiving predialysis care in a universal health care system have faster disease progression than whites, suggesting that health care system factors have a less influential role than had been thought in explaining black-white differences.

Using a genetic, observational study as a strategy to estimate the potential cost-effectiveness of pharmacological CCR5 blockade in dialysis patients.

BACKGROUND AND OBJECTIVE: Randomized clinical trials are expensive and time consuming. Therefore, strategies are needed to prioritise tracks for drug development. Genetic association studies may provide such a strategy by considering the differences between genotypes as a proxy for a natural, lifelong, randomized at conception, clinical trial. Previously an association with better survival was found in dialysis patients with systemic inflammation carrying a deletion variant of the CC-chemokine receptor 5 (CCR5). We hypothesized that in an analogous manner, pharmacological CCR5 blockade could protect against inflammation-driven mortality and estimated if such a treatment would be cost-effective. METHODS: A genetic screen and treat strategy was modelled using a decision-analytic Markov model, in which patients were screened for the CCR5 deletion 32 polymorphism and those with the wild type and systemic inflammation were treated with pharmacological CCR5 blockers. Kidney transplantation and mortality rates were calculated using patient level data. Extensive sensitivity analyses were performed. RESULTS: The cost-effectiveness of the genetic screen and treat strategy was &OV0556;18 557 per life year gained and &OV0556;21 896 per quality-adjusted life years gained. Concordance between the genetic association and pharmacological effectiveness was a main driver of cost-effectiveness. Sensitivity analyses showed that even a modest effectiveness of pharmacological CCR5 blockade would result in a treatment strategy that is good value for money. CONCLUSION: Pharmacological blockade of the CCR5 receptor in inflamed dialysis patients can be incorporated in a potentially cost-effective screen and treat programme. These findings provide formal rationale for clinical studies. This study illustrates the potential of genetic association studies for drug development, as a source of Mendelian randomized evidence from an observational setting.

Statistical methods for the assessment of prognostic biomarkers(part II): calibration and re-classification.

Calibration is the ability of a prognostic model to correctly estimate the probability of a given event across the whole range of prognostic estimates (for example, 30% probability of death, 40% probability of myocardial infarction, etc.). The key difference between calibration and discrimination is that the latter reflects the ability of a given prognostic biomarker to distinguish a status (died/survived, event/non-event), while calibration measures how much the prognostic estimation of a predictive model matches the real outcome probability (that is, the observed proportion of the event). Re-classification is another measure of prognostic accuracy and it reflects how much a new prognostic biomarker increases the proportion of individuals correctly re-classified as having or not having a given event compared to a previous classification based on an existing prognostic biomarker or predictive model.

Diagnostic methods I: sensitivity, specificity, and other measures of accuracy.

For most physicians, use of diagnostic tests is part of daily routine. This paper focuses on their usefulness by explaining the different measures of accuracy, the interpretation of test results, and the implementation of a diagnostic strategy. Measures of accuracy include sensitivity and specificity. Although these measures are often considered fixed properties of a diagnostic test, in reality they are subject to multiple sources of variation such as the population case mix and the severity of the disease under study. Furthermore, when evaluating a new diagnostic test, it must be compared to a reference standard, although the latter is usually not perfect. In daily practice diagnostic tests are not used in isolation. Several issues will influence the interpretation of their results. First, clinicians have a prior assumption about the patient's chances of having the disease under investigation, based on the patient's characteristics, symptoms, and the disease prevalence in similar populations. Second, diagnostic tests are usually part of a diagnostic strategy. Therefore, it is not sufficient to determine the accuracy of a single test; one also needs to determine its additional value to the patient's diagnosis, treatment, or outcome as part of a diagnostic strategy.

Subjective global assessment of nutritional status is strongly associated with mortality in chronic dialysis patients.

BACKGROUND: The subjective global assessment of nutritional status (SGA) is used to assess the nutritional status of chronic dialysis patients, but longitudinal data in relation to mortality risk are lacking. OBJECTIVE: Our objective was to study the long-term and time-dependent associations of the SGA with mortality risk in chronic dialysis patients. DESIGN: In a prospective, longitudinal, observational, multicenter study of incident dialysis patients, the 7-point SGA [7 = normal nutritional status; 1 = severe protein-energy wasting (PEW)] was assessed 3 and 6 mo after the start of dialysis and subsequently every 6 mo during 7 y of follow-up. With Cox regression analysis, we calculated hazard ratios (HRs) of the baseline and time-dependent SGA measurements, adjusted for age, sex, treatment modality, primary kidney diseases, and comorbidity. RESULTS: In total, 1601 patients were included [mean (+/-SD) age: 59 +/- 15 y; 61% men; 23% with moderate PEW (SGA(4-5)), and 5% with severe PEW (SGA(1-3))]. There was a dose-dependent trend of the 7-point SGA with mortality. Compared with a normal nutritional status at baseline, SGA(4-5) (HR: 1.6; 95% CI: 1.3, 1.9) and SGA(1-3) (HR: 2.1; 95% CI: 1.5, 2.8) were associated with an increase in 7-y mortality. Time-dependently, these associations were stronger: SGA(4-5) (HR: 2.1; 95% CI: 1.7, 2.5) and SGA(1-3) (HR: 5.0; 95% CI: 3.8, 6.5). CONCLUSIONS: In dialysis patients, PEW at baseline assessed with SGA was associated with a 2-fold increased mortality risk in 7 y of follow-up. Time-dependently, this association was even stronger, which indicated that PEW was associated with a remarkably high risk of short-term mortality. These data imply that the 7-point SGA may validly distinguish different degrees of PEW associated with increasing risks of mortality.

Association between a self-rated health question and mortality in young and old dialysis patients: a cohort study.

BACKGROUND: Self-rated health (SRH) has been shown to predict mortality in large community-based studies; however, large clinical-based studies of this topic are rare. We assessed whether an SRH item predicts mortality in a large sample of incident dialysis patients beyond sociodemographic, disease, and clinical measures and possible age interaction. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,443 predominantly white patients from 38 dialysis centers in The Netherlands participating in the Netherlands Cooperative Study on the Adequacy of Dialysis-2 between 1997 and 2004. PREDICTOR: SRH score completed at 3 months after the start of dialysis therapy (baseline). OUTCOMES & MEASUREMENTS: Cox proportional hazards model estimated the association between SRH and all-cause mortality. Interaction of SRH with age (<65 and >/=65 years) was examined in an additive model. RESULTS: Mean age of patients was 59.6 +/- 14.8 years, with 61% men and 69% married/living together. Mean follow-up was 2.7 +/- 1.8 years. Deaths per SRH group in the multivariate analyses sample: excellent/very good (9 of 63 patients; 14.3%), good (148 of 473 patients; 31.3%), fair (194 of 508 patients; 38.2%), and poor (45 of 71 patients; 63.4%). Patients with poor, fair, or good health ratings had a greater mortality risk than those with excellent/very good health ratings (adjusted hazard ratio [HR(adj)], 3.56; 95% confidence interval [CI], 1.71 to 7.42; HR(adj), 2.09; 95% CI, 1.06 to 4.12; HR(adj), 1.87; 95% CI, 0.95 to 3.70, respectively) independent of a range of risk factors. No age interaction with SRH was found. LIMITATIONS: Although the SRH-mortality association remained strong despite extensive adjustments, unknown residual confounding could still exist. CONCLUSION: SRH is an independent predictor of mortality in incident dialysis patients. Patients with poor SRH in both age strata had a significantly increased risk of mortality even after controlling for demographic and clinical confounders. Patient self-assessment of health can be an invaluable and economical complement to clinical measures in risk assessment.

Effect of intrauterine growth restriction on kidney function at young adult age: the Nord Trøndelag Health (HUNT 2) Study.

BACKGROUND: The hypothesis of intrauterine origin of adult disease is debated. We tested whether intrauterine growth restriction is associated with later kidney function. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 7,457 Norwegian adults aged 20 to 30 years participating in the population-based Nord Trøndelag Health Study (1995-1997) with data for birth weight, gestational age, and maternal and perinatal risk factors registered at the Medical Birth Registry of Norway. PREDICTOR: Birth weight expressed as an SD score (SDS) to adjust for gestational age and sex. Subjects with a birth weight SDS less than -2.0, -2.0 to -1.3, and -1.3 to 1.3 were defined as very small, small, and appropriate for gestational age, corresponding to less than the 3rd, 3rd to 10th, and 10th to 90th percentiles, respectively. OUTCOME & MEASUREMENTS: Kidney function estimated using the Cockcroft-Gault and isotope dilution mass spectrometry-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. Values less than the sex-specific 10th percentile were defined as low-normal kidney function. RESULTS: Compared with men with birth weight appropriate for gestational age (n = 2,755), odds ratios for low-normal creatinine clearance (<100 mL/min) were 1.66 (95% confidence interval [CI], 1.16 to 2.37) if small for gestational age (n = 261) and 2.40 (95% CI, 1.46 to 3.94) if very small for gestational age (n = 101). Kidney function estimated using the MDRD Study equation gave similar results. Women (n = 3,126, 283, and 112, respectively) had odds ratios of 1.65 (95% CI, 1.17 to 2.35) and 2.00 (95% CI, 1.21 to 3.29) for low-normal creatinine clearance (<80 mL/min), whereas the association was not significant using the MDRD Study equation. Using linear regression, creatinine clearance decreased by 4.0 mL/min (95% CI, 3.3 to 4.6) in men and 2.9 mL/min (95% CI, 2.2 to 3.5) in women per 1-SDS decrease. Adjusting for possible confounders did not influence results. LIMITATIONS: Selection bias could be a problem because the participation rate was 49%, but there were no statistically significant differences between participants and nonparticipants regarding maternal and perinatal characteristics. Adjusting kidney function for body size can be a special problem in people with intrauterine growth restriction. CONCLUSIONS: Although effects were still small in young adulthood, intrauterine growth restriction was significantly associated with low-normal kidney function. The effect was weaker and less consistent in women compared with men.

A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy.

Radiotherapy is often used in Graves' ophthalmopathy, but its efficacy has been doubted. We compared its efficacy with sham irradiation in mild ophthalmopathy. In a double-blind randomized trial, 44 patients received orbital irradiation, and 44 were sham-irradiated. The primary outcome was assessed using major and minor criteria. As secondary outcome, we used a disease-specific quality of life questionnaire (the GO-QoL) and compared cost-effectiveness and need for follow-up treatment. The primary outcome was successful in 23 of 44 (52%) irradiated patients vs. 12 of 44 (27%) sham-irradiated patients at 12 months after treatment (relative risk, 1.9; 95% confidence interval, 1.1-3.4; P = 0.02). Radiotherapy was effective in improving eye muscle motility and decreasing the severity of diplopia. However, quality of life improved similarly in both groups. In the radiotherapy group there was less need for follow-up treatment; 66% vs. 84% of the patients needed further treatment (P = 0.049). Retrobulbar irradiation did not prevent worsening of ophthalmopathy, which occurred in 14% of the irradiated and 16% of the sham-irradiated patients. Radiotherapy is an effective treatment in mild ophthalmopathy. However, the improvement upon irradiation may not be associated with an increase in quality of life or a reduction in treatment costs.