Cynthia J Janmaat

Effect of glomerular filtration rate at dialysis initiation on survival in patients with advanced chronic kidney disease: what is the effect of lead-time bias?

Purpose Current clinical guidelines recommend to initiate dialysis in the presence of symptoms or signs attributable to kidney failure, often with a glomerular filtration rate (GFR) of 5–10 mL/min/1.73 m2. Little evidence exists about the optimal kidney function to start dialysis. Thus far, most observational studies have been limited by lead-time bias. Only a few studies have accounted for lead-time bias, and showed contradictory results. We examined the effect of GFR at dialysis initiation on survival in chronic kidney disease patients, and the role of lead-time bias therein. We used both kidney function based on 24-hour urine collection (measured GFR [mGFR]) and estimated GFR (eGFR). Materials and methods A total of 1,143 patients with eGFR data at dialysis initiation and 852 patients with mGFR data were included from the NECOSAD cohort. Cox regression was used to adjust for potential confounders. To examine the effect of lead-time bias, survival was counted from the time of dialysis initiation or from a common starting point (GFR 20 mL/min/1.73 m2), using linear interpolation models. Results Without lead-time correction, no difference between early and late starters was present based on eGFR (hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.81–1.3). However, after lead-time correction, early initiation showed a survival disadvantage (HR between 1.1 [95% CI 0.82–1.48] and 1.33 [95% CI 1.05–1.68]). Based on mGFR, the potential survival benefit for early starters without lead-time correction (HR 0.8, 95% CI 0.62–1.03) completely disappeared after lead-time correction (HR between 0.94 [95% CI 0.65–1.34] and 1.21 [95% CI 0.95–1.56]). Dialysis start time differed about a year between early and late initiation. Conclusion Lead-time bias is not only a methodological problem but also has clinical impact when assessing the optimal kidney function to start dialysis. Therefore, lead-time bias is extremely important to correct for. Taking account of lead-time bias, this controlled study showed that early dialysis initiation (eGFR >7.9, mGFR >6.6 mL/min/1.73 m2) was not associated with an improvement in survival. Based on kidney function, this study suggests that in some patients, dialysis could be started even later than an eGFR <5.7 and mGFR <4.3 mL/min/1.73 m2.

Lower serum calcium is independently associated with CKD progression

Disturbances in calcium metabolism are common in individuals with chronic kidney disease (CKD), but whether they are associated with subsequent kidney function decline is less clear. In a CKD 3–5 cohort of 15,755 adult citizens of Stockholm with creatinine tests taken during 2006–2011 and concurrent calcium testing at cohort entry, we investigated the association between baseline serum calcium and the subsequent change in estimated glomerular filtration rate (eGFR, by CKD-EPI) decline using linear mixed models. Mean (SD) baseline corrected serum calcium was 9.6 (0.5) mg/dL. Mean (95%-confidence interval [CI]) eGFR decline was −0.82 (−0.90; −0.74) mL/min/1.73 m2/year. In advanced CKD stages, higher baseline serum calcium was associated with less rapid kidney function decline. The adjusted change (95%-CI) in eGFR decline associated with each mg/dL increase in baseline serum calcium was −0.10 (−0.28; 0.26), 0.39 (0.07; 0.71), 0.34 (−0.02; 0.70) and 0.68 (0.36; 1.00) mL/min/1.73 m2/year for individuals in CKD stage 3a, 3b, 4, and 5, respectively. In a subgroup of patients using vitamin D supplements, the association between baseline serum calcium and CKD progression was eliminated, especially in CKD stage 3b and 4. To conclude, in individuals with CKD stage 3b to 5, lower baseline corrected serum calcium, rather than higher baseline serum calcium, associated with a more rapid CKD progression. Lower serum corrected calcium seems to be indicative for vitamin D deficiency.

Pitfalls of linear regression for estimating slopes over time and how to avoid them by using linear mixed-effects models

Clinical epidemiological studies often focus on investigating the underlying causes of disease. For instance, a nephrologist may be interested in the association between blood pressure and the development of chronic kidney disease (CKD). However, instead of focusing on the mere occurrence of CKD, the decline of kidney function over time might be the outcome of interest. For examining this kidney function trajectory, patients are typically followed over time with their kidney function estimated at several time points. During follow-up, some patients may drop out earlier than others and for different reasons. Furthermore, some patients may have greater kidney function at study entry or faster kidney function decline than others. Also, a substantial heterogeneity may exist in the number of kidney function estimates available for each patient. This heterogeneity with respect to kidney function, dropout and number of kidney function estimates is important to take into account when estimating kidney function trajectories. In general, two methods are used in the literature to estimate kidney function trajectories over time: linear regression to estimate individual slopes and the linear mixed-effects model (LMM), i.e. repeated measures analysis. Importantly, the linear regression method does not properly take into account the above-mentioned heterogeneity, whereas the LMM is able to retain all information and variability in the data. However, the underlying concepts, use and interpretation of LMMs are not always straightforward. Therefore we illustrate this using a clinical example and offer a framework of how to model and interpret the LMM.

No consensus on physicians’ preferences on vascular access management after kidney transplantation: Results of a multi-national survey:

Objective: Arteriovenous fistulas for hemodialysis vascular access are a burden for the cardiovascular system. After successful kidney transplantation, prophylactic arteriovenous fistula ligation may improve cardiac outcomes; however, evidence is scarce. This survey investigates physicians’ preference for management of arteriovenous fistulas and identifies the factors associated with preference for either arteriovenous fistula ligation or maintenance. Materials and methods: A survey was sent to members of eight national and international Nephrology and Vascular Surgery societies. The survey comprised eight case vignettes of asymptomatic patients with a functioning arteriovenous fistula after kidney transplantation. Characteristics possibly associated with treatment preferences were arteriovenous fistula flow, left ventricular ejection fraction, and patient age. Respondents were asked to state preference to maintain or ligate the arteriovenous fistula. Linear mixed-effects models were used to investigate the association of treatment preference with case characteristics. Results: A total of 585 surveys were returned. A reduced left ventricular ejection fraction of 30% (beta 0.60, 95% confidence interval 0.55; 0.65) and a high flow of 2500 mL/min (beta 0.46, 95% confidence interval 0.41; 0.51) were associated with a higher preference for arteriovenous fistula ligation. Disagreement among respondents was considerable, as in four out of eight cases less than 70% of respondents agreed on the arteriovenous fistula management strategy. Conclusion: Although respondents recognize a reduced left ventricular ejection fraction and a high flow as the risk factors, the high disagreement on management preferences suggests that evidence is inconclusive to recommend arteriovenous fistula ligation or maintenance after kidney transplantation. More research is needed to determine optimal arteriovenous fistula management after successful kidney transplantation.

Decline of kidney function during the pre-dialysis period in chronic kidney disease patients: a systematic review and meta-analysis

Purpose Substantial heterogeneity exists in reported kidney function decline in pre-dialysis chronic kidney disease (CKD). By design, kidney function decline can be studied in CKD 3–5 cohorts or dialysis-based studies. In the latter, patients are selected based on the fact that they initiated dialysis, possibly leading to an overestimation of the true underlying kidney function decline in the pre-dialysis period. We performed a systematic review and meta-analysis to compare the kidney function decline during pre-dialysis in CKD stage 3–5 patients, in these two different study types. Patients and methods We searched PubMed, EMBASE, Web of Science and Cochrane to identify eligible studies reporting an estimated glomerular filtration rate (eGFR) decline (mL/min/1.73 m2) in adult pre-dialysis CKD patients. Random-effects meta-analysis was performed to obtain weighted mean annual eGFR decline. Results We included 60 studies (43 CKD 3–5 cohorts and 17 dialysis-based studies). The meta-analysis yielded a weighted annual mean (95% CI) eGFR decline during pre-dialysis of 2.4 (95% CI: 2.2, 2.6) mL/min/1.73 m2 in CKD 3–5 cohorts compared to 8.5 (95% CI: 6.8, 10.1) in dialysis-based studies (difference 6.0 [95% CI: 4.8, 7.2]). Conclusion To conclude, dialysis-based studies report faster mean annual eGFR decline during pre-dialysis than CKD 3–5 cohorts. Thus, eGFR decline data from CKD 3–5 cohorts should be used to guide clinical decision making in CKD patients and for power calculations in randomized controlled trials with CKD progression during pre-dialysis as the outcome.