Dorothea Nitsch

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.

BACKGROUND Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. METHODS In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. FINDINGS The analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. INTERPRETATION eGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. FUNDING Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.Background A comprehensive evaluation of the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality is required for assessment of the impact of kidney function on risk in the general population, with implications for improving the definition and staging of chronic kidney disease (CKD).

Tenofovir-Associated Kidney Toxicity in HIV-Infected Patients: A Review of the Evidence

Tenofovir (TDF) is an effective and widely used treatment for both human immunodeficiency virus (HIV) and hepatitis B virus infection. Although studies suggest that TDF has a low overall toxicity profile and only a modest effect on estimated glomerular filtration rate, numerous case reports have since appeared in the literature describing TDF-associated renal tubular dysfunction, and this is now a significant source of HIV-related referrals to nephrologists. The main target of toxicity appears to be the proximal tubule, and in severe cases, patients can develop renal Fanconi syndrome. We review findings from recent studies in this area performed by ourselves and others and discuss our direct experience as practicing nephrologists. In particular, we discuss: (1) the nature and extent of TDF-associated kidney toxicity in the HIV-infected population, (2) potential underlying mechanisms of toxicity in the proximal tubule, (3) risk factors for developing tubular dysfunction, and (4) suggested strategies to monitor patients on TDF therapy.

Gender and telomere length: Systematic review and meta-analysis

BACKGROUND It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. METHODS We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. RESULTS Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. CONCLUSIONS Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

CKD and Mortality Risk in Older People: A Community-Based Population Study in the United Kingdom

BACKGROUND The prevalence of chronic kidney disease (CKD) increases with age; however, the prognostic significance in older people is uncertain. This study aims to determine the association of CKD with all-cause and cardiovascular mortality in community-dwelling older people 75 years and older. STUDY DESIGN Cohort study of people 75 years and older recruited in 1994 to 1999 to 1 arm of a trial of multidimensional health assessment with mortality follow-up. SETTING & PARTICIPANTS 53 general practices in Great Britain. 15,336 (73%) of those eligible participated. 13,177 (86%) had serum creatinine measured at baseline. MAIN FACTOR Estimated glomerular filtration rate (eGFR). OUTCOMES All-cause and cardiovascular mortality. MEASUREMENTS eGFR derived from serum creatinine level using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation in milliliters per minute per 1.73 m(2); dipstick proteinuria. Mortality by linkage to national death registration and death certification. RESULTS After a median follow-up of 7.3 years (interquartile range, 5.0), 7,633 (58%) had died, 42% of cardiovascular causes. In the first 2 years of follow-up, adjusted hazard ratios for all-cause mortality in eGFR bands of 45 to 59, 30 to 44, and less than 30 compared with eGFR greater than 60 mL/min/1.73 m(2) were 1.13 (95% confidence interval, 0.93 to 1.37), 1.69 (95% confidence interval, 1.26 to 2.28), and 3.87 (95% confidence interval, 2.78 to 5.38) in men and 1.14 (95% confidence interval, 0.93 to 1.40), 1.33 (95% confidence interval, 1.06 to 1.68), and 2.44 (95% confidence interval, 1.68 to 3.56) in women, respectively. Hazard ratios were greater for cardiovascular mortality and lower after 2 years. Dipstick proteinuria was independently associated with all-cause, but not cardiovascular, mortality risk in both sexes. LIMITATIONS Single serum creatinine measurement, no calibration of serum creatinine, MDRD Study equation not validated in older people. CONCLUSION As kidney function decreases, there is a graded and independent increase in all-cause and cardiovascular mortality risk in older people 75 years and older, especially in men and those with eGFR less than 45 mL/min/1.73 m(2). Dipstick proteinuria did not add to cardiovascular mortality risk in this elderly population. In older people, identification and management of CKD should prioritize the smaller numbers with more severe CKD.

A structured approach to modelling the effects of binary exposure variables over the life course

Background There is growing interest in the relationship between time spent in adverse circumstances across life course and increased risk of chronic disease and early mortality. This accumulation hypothesis is usually tested by summing indicators of binary variables across the life span to form an overall score that is then used as the exposure in regression models for health outcomes. This article highlights potential issues in the interpretation of results obtained from such an approach. Methods We propose a model-building framework that can be used to formally compare alternative hypotheses on the effect of multiple binary exposure measurements collected across the life course. The saturated model where the order and value of the binary variable at each time point influence the outcome of interest is compared with nested alternative specifications corresponding to the critical period, cumulative risk or hypotheses about the effect of changes in environment. This framework is illustrated with data on adult body mass index and socioeconomic position measured once in childhood and twice in adulthood from the Medical Research Council National Survey of Health and Development, using a series of liner regression models. Results We demonstrate how analyses that only consider the association of a cumulative score with a later outcome may produce misleading results. Conclusion We recommend comparing a set of nested models—each corresponding to the accumulation, critical period and effect modification hypotheses—to an all-inclusive (saturated) model. This approach can provide a formal and clearer understanding of the relative merits of these alternative hypotheses.

Effect of early intervention on 5-year outcome in non-affective psychosis

BACKGROUND Early specialised care may improve short-term outcome in first-episode non-affective psychosis, but it is unclear if these benefits endure. AIMS To assess the long-term effect of early intervention in psychosis. METHOD Individuals with first-episode psychosis were randomised to specialised care or care as usual (trial number: ISRCTN73679874). Outcome after 5 years was assessed by case-note review. RESULTS There were no significant differences in the admission rate (coefficient 0.096, 95% CI -0.550 to 0.742, P = 0.770) or the mean number of bed days (coefficient 6.344, 95% CI -46 to 58.7, P = 0.810). CONCLUSIONS These findings that specialist intervention did not markedly improved outcome at 5 years accord with those from a larger OPUS study. The sample size of this study was small and these results should be generalised with caution. More research is needed.

Role of NADPH Oxidase in Endothelial Ischemia/Reperfusion Injury in Humans

Background— Reactive oxygen species have been implicated in the pathogenesis of ischemia/reperfusion (IR) injury. Recent studies suggest that NADPH oxidase may be a source of ROS during IR. Using an in vivo model of endothelial IR injury in the arm, we compared the response to IR in healthy volunteers with that in patients with chronic granulomatous disease. These patients have a molecular lesion in a subunit of NADPH oxidase that renders the enzyme inactive. Methods and Results— Flow-mediated dilatation was used to assess endothelial function in patients with X-linked (NOX2) or autosomal (p47) chronic granulomatous disease. IR injury was induced by 20 minutes of upper limb ischemia followed by reperfusion. Flow-mediated dilatation was determined before IR and after 20 minutes of reperfusion. The response to IR in chronic granulomatous disease patients was compared with that in age- and sex-matched healthy control subjects. Flow-mediated dilatation was expressed as mean and compared statistically with mixed linear models. IR caused a significant reduction in flow-mediated dilatation in control subjects (−5.1%; 95% confidence interval, 6.3 to 3.%; P<0.001; n=11). IR had no effect on endothelial function in NOX2-chronic granulomatous disease patients (−0.9; 95% confidence interval, −2.1 to 0.3; P=0.12; n=11). Similarly, IR-induced reduction in flow-mediated dilatation was not observed in p47-chronic granulomatous disease patients (−1.5%; 95% confidence interval, −3.1 to 0.2; P=0.08; n=6) in contrast to healthy control subjects (−6.5%; 95% confidence interval, −8.2 to −4.9%; P<0.001; n=6). Conclusions— These data indicate, for the first time in humans in vivo, that reactive oxygen species produced by NADPH oxidase are determinants of endothelial function after IR injury in humans. These findings have implications for the design of strategies to limit clinical IR injury.

Blood Pressure and Mortality Risk on Peritoneal Dialysis

BACKGROUND The association of baseline blood pressure (BP) and mortality in incident peritoneal dialysis patients has not been adequately studied. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS 2,770 patients on PD therapy at 180 days from start of renal replacement therapy in England and Wales between 1997 and 2004. PREDICTORS Systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) measured in the first 6 months of renal replacement therapy and other baseline demographic and laboratory variables. OUTCOMES All-cause mortality was studied using time-stratified Cox regression models (to account for nonproportionality) dividing follow-up time into 4 intervals: year 1 (days 180 to 365), years 2 to 3, years 4 to 5, and years 6+. Interactions between BP components and transplant waitlist and diabetes status were explored. RESULTS Median follow-up was 3.7 years (range, 0.1 to 9.9 years), and 1,104 deaths were observed. In fully adjusted analyses, greater SBP, DBP, MAP, and PP were associated with decreased mortality in the first year, but greater SBP and PP were associated with increased late mortality (in years 6+). However, in the subgroup of patients placed on the transplant waitlist within 6 months of starting renal replacement therapy, greater SBP, DBP, MAP, and PP were not associated with decreased mortality in the first year. LIMITATIONS Exclusion of 3,086 patients because of missing BP data. No data were available for cardiac function or antihypertensive medication. CONCLUSIONS Although greater SBP, DBP, MAP, and PP appear protective against early mortality in the overall cohort, this effect is not seen in patients registered on the national transplant waiting list within 6 months of starting renal replacement therapy.

How good is probabilistic record linkage to reconstruct reproductive histories? Results from the Aberdeen children of the 1950s study

BackgroundProbabilistic record linkage is widely used in epidemiology, but studies of its validity are rare. Our aim was to validate its use to identify births to a cohort of women, being drawn from a large cohort of people born in Scotland in the early 1950s.MethodsThe Children of the 1950s cohort includes 5868 females born in Aberdeen 1950–56 who were in primary schools in the city in 1962. In 2001 a postal questionnaire was sent to the cohort members resident in the UK requesting information on offspring. Probabilistic record linkage (based on surname, maiden name, initials, date of birth and postcode) was used to link the females in the cohort to birth records held by the Scottish Maternity Record System (SMR 2).ResultsWe attempted to mail a total of 5540 women; 3752 (68%) returned a completed questionnaire. Of these 86% reported having had at least one birth. Linkage to SMR 2 was attempted for 5634 women, one or more maternity records were found for 3743. There were 2604 women who reported at least one birth in the questionnaire and who were linked to one or more SMR 2 records. When judged against the questionnaire information, the linkage correctly identified 4930 births and missed 601 others. These mostly occurred outside of Scotland (147) or prior to full coverage by SMR 2 (454). There were 134 births incorrectly linked to SMR 2.ConclusionProbabilistic record linkage to routine maternity records applied to population-based cohort, using name, date of birth and place of residence, can have high specificity, and as such may be reliably used in epidemiological research.

Renal outcome in adults with renal insufficiency and irregular asymmetric kidneys

BackgroundThe commonest cause of end-stage renal failure (ESRF) in children and young adults is congenital malformation of the kidney and urinary tract. In this retrospective review, we examine whether progression to ESRF can be predicted and whether treatment with angiotensin converting enzyme inhibitors (ACEI) can delay or prevent this.MethodsWe reviewed 78 patients with asymmetric irregular kidneys as a consequence of either primary vesico-ureteric reflux or renal dysplasia (Group 1, n = 44), or abnormal bladder function (Group 2, n = 34). Patients (median age 24 years) had an estimated GFR (eGFR) < 60 ml/min/1.73 m2 with at least 5 years of follow up (median 143 months). 48 patients received ACEI. We explored potential prognostic factors that affect the time to ESRF using Cox-regression analyses.ResultsAt start, mean (SE) creatinine was 189 (8) μmol/l, mean eGFR 41 (1) ml/min 1.73 m2, mean proteinuria 144 (14) mg/mmol creatinine (1.7 g/24 hrs). Of 78 patients, 36 (46%) developed ESRF, but none of 19 with proteinuria less than 50 mg/mmol and only two of 18 patients with eGFR above 50 ml/min did so. Renal outcome between Groups 1 and 2 appeared similar with no evidence for a difference. A benefit in favour of treatment with ACEI was observed above an eGFR of 40 ml/min (p = 0.024).ConclusionThe similar outcome of the two groups supports the nephrological nature of progressive renal failure in young men born with abnormal bladders. There is a watershed GFR of 40–50 ml/min at which ACEI treatment can be successful at improving renal outcome.