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?

Abstract

PurposeCurrent 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 methodsA 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.ResultsWithout 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.ConclusionLead-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.

Timing of dialysis initiation to reduce mortality and cardiovascular events in advanced chronic kidney disease: nationwide cohort study

“…Despite extensive previous literature, evidence on whether an optimal glomerular filtration rate to start dialysis exists, and if so where it lies, is lacking. Previous observational studies that attempted to investigate multiple estimated glomerular filtration rate (eGFR) strategies have been limited by insufficient power, 11 12 13 immortal time bias, 14 15 16 17 or lead time and selection biases. 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 In 2010 the Initiating Dialysis Early and Late (IDEAL) trial showed that a strategy to start dialysis at an eGFR of 10-14 mL/min/1.73 m 2 was not superior to one of waiting until symptoms develop or eGFR is 5-7 mL/min/1.73 m 2 .…”

Dialysis Start Timing: Development and Validation of Start Scoring Scale

“…Однако, они оказались противоречивыми: большие относительные риски смерти были связаны с большей измеренной СКФ, но с меньшей расчетной СКФ [5]. Анализ исследования NECOSAD продемонстрировал различный эффект коррекции по предвзятости пре-ждевременного старта для измеренной СКФ в срав-нении с расчетной СКФ, при этом в исследовании присут ствовало серьезное ограничение: пациенты, лечившиеся на диализном катетере, были исключены из исследования (а это возможный маркер экстренного старта) [25]. В другом анализе того же регистра пред-диализное снижение измеренного, но нерасчетного СКФ было фактором риска смерти на диализе [26].…”

Where to look for the most frequent biases?

“…In nephrology, it has become widely known as a problem of cohort studies comparing policies of early and late start of dialysis. When patients start dialysis at a higher eGFR without severe uraemic signs and symptoms, and their survival is compared to those starting dialysis at a lower eGFR with severe uraemic signs and symptoms, then this comparison may suffer from lead‐time bias favouring those with an early start . Some studies have attempted to take lead‐time bias into account by estimating the date at which patients had a predefined level of eGFR before dialysis start and then counting survival time in both early and late starters from that date onwards …”