S. Karger AG

The internal validity of an epidemiological study can be affected by <i>random error</i> and <i>systematic error</i>. Random error reflects a problem of precision in assessing a given exposure-disease relationship and can be reduced by increasing the sample size. On the other hand, systematic error or bias reflects a problem of validity of the study and arises because of any error resulting from methods used by the investigator when recruiting individuals for the study, from factors affecting the study participation <i>(selection bias)</i> or from systematic distortions when collecting information about exposures and outcomes <i>(information bias)</i>. Another important factor which may affect the internal validity of a clinical study is <i>confounding</i>. In this article, we focus on two categories of bias: selection bias and information bias. Confounding will be described in a future article of this series.

<i>Background/Aims:</i> Hyperphosphatemia is an important clinical consequence of renal failure, and its multiple adverse systemic effects are associated with significantly increased risks of morbidity and mortality in dialysis patients. Existing oral phosphate binders have not permitted control of serum phosphate within currently accepted guidelines. This study compares lanthanum carbonate with calcium carbonate for control of serum phosphate in hemodialysis patients. <i>Methods:</i> In this European multicentre study, 800 patients were randomised to receive either lanthanum or calcium carbonate and the dose titrated over 5 weeks to achieve control of serum phosphate. Serum levels of phosphate, calcium and parathryoid hormone were followed over the following 20 weeks. <i>Results:</i> Around 65% of patients in each group achieved phosphate control, but in the calcium carbonate group this was at the expense of significant hypercalcemia (20.2% of patients vs. 0.4%). Consequently, calcium x phosphate product tended to be better controlled in the lanthanum group. <i>Conclusion:</i> This 6-month study demonstrates that serum phosphate control with lanthanum carbonate (750–3,000 mg/day) is similar to that seen with calcium carbonate (1,500–9,000 mg/day), but with a significantly reduced incidence of hypercalcemia. Lanthanum carbonate is well tolerated and may be more effective in reducing calcium x phosphate product than calcium carbonate.

The development and use of consensus criteria for acute kidney injury (AKI) diagnosis and the inclusion of recently identified markers of renal parenchymal damage as endpoints in clinical trials have improved the ability of physicians to compare the incidence and severity of AKI across patient populations, provided targets for testing new treatments, and may increase insight into the mechanisms of AKI. To date, these markers have not consistently translated into important clinical outcomes. Is that because these markers of renal injury/dysfunction are measurements of process of care (and not indicative of persistently impaired renal function), or is it because patients do actually recover from AKI? Physicians currently have limited ability to measure renal function reserve, and the ultimate consequence of a case of AKI on long-term morbidity remains unclear. There is little doubt that groups of patients who develop AKI have worse outcomes than groups of patients who do not, but investigators are now realizing the value of measuring <i>clinically meaningful</i> renal endpoints in all subjects enrolled in AKI clinical trials. Important examples of these outcomes include persistently impaired renal function, new hemodialysis, and death. We propose that these major adverse kidney events (MAKE) be included in all effectiveness clinical trials. Adaptation of the MAKE composite assessed 30, 60, or 90 days following AKI (i.e., MAKE30 or MAKE90) will improve our capacity to understand and treat AKI and may also provide a consensus composite to allow comparison of different interventions. Primary endpoints for phase I and II clinical trials, on the other hand, should continue to use continuous markers of renal injury/dysfunction as well as ‘hard' clinical outcomes in order to generate meaningful data with limited subject exposure to untested treatments. By doing so, investigators may assess safety without requiring large sample sizes, demonstrate treatment effect of an unknown therapeutic, and power subsequent studies. In contrast, phase III trials should include consensus AKI criteria and more important subsequent clinical outcomes, such as MAKE90, as primary endpoints.

<i>Background:</i> Abnormalities of the aortic valve occur with increased frequency in patients with renal failure and may contribute to the observed excess cardiovascular mortality. Little data exist on the rate at which aortic stenosis progresses in this patient group. <i>Methods:</i> A retrospective case-control study was designed to compare the rate of progression of aortic stenosis in dialysis patients with that in sex-matched controls. Dialysis patients with aortic stenosis were identified by a search of the echocardiography database. Twenty-eight dialysis patients were compared to 56 sex-matched controls, all of whom had aortic stenosis on at least two echocardiograms 6 months apart. Changes in mean and peak transvalvular gradient as well as valve area were calculated from echocardiographic data and compared. <i>Results:</i> Aortic stenosis progressed more rapidly in the dialysis patients than in the controls when measured by change in valve area (–0.19 vs. –0.07 cm²/year; p < 0.001) and change in peak transvalvular gradient (6.5 vs. 3.9 mm Hg/ year; p = 0.04). There was also a trend towards more rapid progression of mean transvalvular gradient (4.9 vs. 2.5 mm Hg/year; p = 0.052). On multivariate linear regression analysis, only end-stage renal failure (p = 0.02) and baseline valve area (p = 0.04) predicted accelerated progression of aortic stenosis. <i>Conclusions:</i> Aortic stenosis progressed more rapidly in the presence of renal failure. The time frames for review and operation in dialysis patients should be shorter than for the general population.

<i>Background:</i> Control of serum phosphate over the long term is essential in patients with end-stage renal disease. Six-month and 2-year extensions to a 6-month study evaluated the long-term safety, tolerability and efficacy of the new phosphate binder lanthanum carbonate. <i>Methods:</i> Patients who participated in a 6-month, randomized trial comparing lanthanum carbonate with calcium carbonate were eligible for a 24-week, open-label extension. Lanthanum carbonate-treated patients continued taking their established maintenance dose (‘continued-lanthanum group’) and calcium carbonate-treated patients switched to lanthanum carbonate, 375–3,000 mg/day (‘switch group’). Patients could also enter a further 2-year extension. Efficacy parameters, including serum phosphate, were monitored. <i>Results:</i> Mean serum phosphate was ∼1.80 mmol/l throughout the trial. The percentage of patients with controlled serum phosphate (≤1.80 mmol/l) after the 6-month extension was 63.3 and 58.4% in the continued-lanthanum and switch groups, respectively; after the 2-year extension, 54.4% of patients had controlled serum phosphate. After discontinuation of calcium carbonate and initiation of lanthanum carbonate, the hypercalcemia incidence was 2.7%, compared with 20.2% during the double-blind phase. Calcium × phosphate product was maintained at an acceptable level. Lanthanum carbonate was well tolerated; adverse events were mild/moderate and mainly gastrointestinal. <i>Conclusions:</i> Lanthanum carbonate maintains effectiveness with continued tolerability for up to 3 years.

<i>Background:</i> An evaluation of exercise counseling practices among nephrologists in 2001 demonstrated few clinicians assessing patients’ levels of physical activity (PA) and counseling to increase activity. Recent Kidney Disease Outcomes Quality Initiative (KDOQI) cardiovascular guidelines recommended that nephrologists counsel patients to increase PA. Our objective was to ascertain whether nephrologists’ counseling practices have changed. <i>Methods:</i> We administered a 30-item survey regarding exercise counseling to nephrologists attending the ASN meeting in 2007. Some questions were adapted from a prior survey administered in 2001 to assess differences in practice patterns compared to 6 years earlier. <i>Results:</i> Participants answered questions regarding opinions and practices relevant to PA (n = 198), KDOQI guidelines, self-reported PA, and demographic information (n = 173). Participants were 44 ± 11 years of age, 48% practicing in the USA, and 76% male. In multivariate analysis, older nephrologists (OR; 95% CI) (3.3; 1.2–9.0) and those more physically active (5.5; 2.0–14) were more likely to ask and counsel patients about PA. Opinions associated with less counseling behavior included lack of confidence in ability to discuss PA (0.2; 0.05–0.5). Multivariate comparison to previous respondents (n = 503) showed current nephrologists were not asking and counseling more (1.2; 0.81–1.8). <i>Conclusion:</i> Despite new guidelines, counseling behavior has not increased. Published guidelines are insufficient to reach younger nephrologists.

Glomerular podocytes are known to regulate proteinuria and podocyturia correlated with proteinuria. Podocyturia, the urinary excretion of viable podocytes (glomerular epithelial cells), has been associated with proteinuria in preeclampsia. This study is the first to investigate the time course alterations of podocyturia in patients with preeclampsia (11 cases) and normotensive pregnant women (45 cases). Urinalysis was performed at 35 weeks of gestation, 4 days after delivery, and 1 month after delivery. In patients with preeclampsia, podocyturia was evident at 35 weeks of gestation and 4 days after delivery, while proteinuria had already decreased at 4 days after delivery. At 1 month after delivery, almost no patients exhibited podocyturia. In control cases, proteinuria was not significant throughout the study period. However, 9 of the 45 controls exhibited transient and mild podocyturia at 4 days after delivery without proteinuria or hypertension. Statistics indicated a correlation between urinary podocyte number and blood pressure, but not with proteinuria. In conclusion, podocyturia in preeclampsia is transient and almost synchronous with heavy proteinuria. The results suggest that acute podocyte loss implicates podocyturia as the possible mechanism of proteinuria in women with preeclampsia.

<i>Background:</i>Cardiovascular disease remains the most common cause of mortality in end-stage kidney failure patients with diabetes. To improve blood pressure control, and reduce cardiovascular risk, in 2002 the UK Renal Association Standards’ Committee introduced pre- and post-dialysis target blood pressures of <140/90 and <130/80 mm Hg, respectively. <i>Methods:</i> We audited blood pressure control and symptomatic intradialytic hypotension during 1 week in the eleven renal centres in the Greater London Urban Area in 2,193 patients, capturing 6,579 haemodialysis sessions. <i>Results:</i> Although 73.9% of the 658 diabetic patients were prescribed antihypertensive medications, compared to 57.8% of the 1,535 non-diabetic patients (p < 0.001), both the mean pre- and post-dialysis blood pressures were greater in the diabetic patients: before dialysis 152 ± 23/77 ± 13 versus 144 ± 23/79 ± 13 mm Hg and after dialysis 138 ± 24/71 ± 12 versus 132 ± 26/73 ± 13 mm Hg, and fewer diabetic patients achieved the pre- and post-dialysis blood pressure targets: 28.6 versus 40.8% and 37.9 versus 46.3%, respectively (p < 0.01). In addition, more diabetic patients suffered symptomatic intradialytic hypotension, 20.3 versus 14.9% (p < 0.01), associated with greater interdialytic weight gains. <i>Conclusion:</i> Diabetic haemodialysis patients had higher blood pressures, both before and after dialysis, associated with greater interdialytic weight gains and more frequent symptomatic intradialytic hypotension.

The prevalence and extent of vascular calcification (VC) increases rapidly with time on dialysis. There is increasing evidence that medial calcification of conduit arteries, without intimal disease, is associated with important abnormalities of vascular compliance and increased risk of cardiovascular death. Coronary artery calcification is also common in end-stage renal disease, but further research is required to determine how much of this calcification is in the form of calcified intimal atherosclerotic plaque and how much in the tunica media. Calcific uraemic arteriolopathy causes a syndrome of ischaemic necrosis of the skin and subcutaneous tissue and appears to be increasing in incidence. At all sites, arterial calcification is a biologically controlled process, with expression in vascular smooth muscle cells of genes usually expressed in osteoblasts and the formation of hydroxyapatite. High extracellular phosphate concentration induces these phenotypic changes in vitro, and much of the clinical evidence supports hyperphosphataemia as the major driver of VC. Whether warfarin treatment plays a role, by inhibiting production of vitamin-K-dependent inhibitors of calcification in humans, remains uncertain but possible. High doses of prescribed calcium-based phosphate binders are associated with VC, whereas use of sevelamer to achieve the same serum phosphate level greatly retards progression of coronary and aortic calcification. The biological mechanism by which positive calcium balance and/or episodes of hypercalcaemia promotes VC remains unclear. Treatment of established calcific uraemic arteriolopathy consists of aggressive reduction of serum calcium × phosphate product; the roles of hyperbaric oxygen, steroid therapy, and non-warfarin anticoagulation remain uncertain.