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?

Figures & data

Figure 1 Lead time based on moment of referral and time of dialysis initiation.

Notes: Lead-time bias tends to favor earlier dialysis initiation, because patients starting dialysis with more residual kidney function enter dialysis earlier in the course of the disease than those starting dialysis with less residual function, and accordingly gain a spurious residual lifetime advantage. Analyzing survival from the moment of referral solves the problem of lead-time bias, as would analyzing from the moment a certain glomerular filtration rate is reached (eg, 20 mL/min/1.73 m², as used in the present study).

Figure 2 Patient-inclusion flowchart for patients with data on mGFR (A) and data on eGFR (B).

Abbreviations: mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtration rate.

Table 1 Patient characteristics

	Total n=852	Moment of dialysis initiation – mGFR			Total n=1,143	Moment of dialysis initiation – eGFR
		Late n=284	Intermediate n=284	Early n=284		Late n=381	Intermediate n=381	Early n=381
Baseline GFR (mL/min/1.73 m^2)	5.6 (±3)	2.5 (±1.4)	5.4 (±0.7)	8.9 (±2.1)	7.1 (±2.8)	4.4 (±1.2)	6.7 (±0.6)	10.2 (±2.3)
Age (years)	61.1 (47.9–70.6)	62.1 (47.8–71.7)	61.8 (49.1–70.8)	59 (47.1–69.1)	62 (50–71.3)	58.3 (46.3–67.9)	62.5 (50.8–72)	66.3 (54.3–74.3)
Sex (% male)	527 (61.9)	171 (60.2)	176 (62)	180 (63.4)	716 (62.6)	201 (52.8)	240 (63)	275 (72.2)
Ethnicity, Caucasian (%)	761 (92.1)	255 (90.7)	258 (93.5)	248 (92.2)	1039 (90.9)	339 (89)	349 (91.6)	351 (92.1)
BMI (kg/m^2)	24.4 (22.1–27.4)	24.1 (22–26.9)	24.4 (22.2–27.3)	24.8 (22.3–28.2)	24.5 (22.2–27.3)	24.4 (22–27.5)	25 (22.7–27.2)	24 (21.9–27.1)
Smokers (%)	195 (23.8)	62 (22.7)	68 (23.9)	65 (23.8)	238 (23.4)	76 (21.7)	81 (24.3)	81 (24.5)
Primary kidney disease (%)
Diabetes mellitus	128 (15)	45 (15.8)	32 (11.3)	51 (18)	170 (14.9)	37 (9.7)	57 (15)	76 (19.9)
Glomerulonephritis	110 (12.9)	36 (12.7)	42 (14.8)	32 (11.3)	142 (12.4)	60 (15.7)	45 (11.8)	37 (9.7)
Renal vascular disease	143 (16.8)	57 (20.1)	41 (14.4)	45 (15.8)	182 (15.6)	59 (15.5)	43 (11.3)	80 (21)
Other	471 (55.3)	146 (51.4)	169 (59.5)	156 (54.9)	649 (56.8)	252 (59.1)	236 (61.9)	188 (49.3)
Khan index (%)
Low	366 (43)	113 (39.8)	140 (49.3)	113 (39.8)	474 (41.5)	212 (55.6)	158 (41.5)	104 (27.3)
Medium	280 (32.9)	102 (35.9)	77 (27.1)	101 (35.6)	374 (32.7)	107 (28.1)	134 (35.2)	133 (34.9)
High	206 (24.2)	69 (24.3)	67 (23.6)	70 (24.6)	295 (25.8)	62 (16.3)	89 (23.4)	144 (37.8)
Medication
ACE inhibitors	144 (16.9)	42 (14.8)	43 (15.1)	59 (20.8)	199 (17.4)	56 (14.7)	72 (18.9)	71 (18.6)
Calcium antagonists	180 (21.1)	43 (15.1)	56 (19.7)	81 (28.5)	280 (24.5)	91 (23.9)	102 (26.8)	87 (22.8)
β-Blockers	159 (18.7)	45 (15.8)	50 (17.6)	64 (22.5)	262 (22.9)	87 (22.8)	92 (24.1)	83 (21.8)
Diuretics	167 (19.6)	40 (14.1)	59 (20.8)	68 (23.9)	273 (23.9)	68 (17.8)	104 (27.3)	101 (26.5)
Systolic blood pressure (mmHg)	149.8 (±23.8)	150.7 (±24.7)	150.3 (±22.7)	148.4 (±24)	150 (±24.1)	150.7 (±24.6)	151.6 (±24.1)	147.7 (±23.5)
Diastolic blood pressure (mmHg)	83.8 (±23.8)	83.9 (±13.8)	85.7 (±12.8)	81.8 (±11.8)	82.9 (±12.8)	85.3 (±13.5)	83.7 (±11.7)	79.6 (±12.5)
Dialysis modality (% HD)	437 (51.3)	167 (58.8)	136 (47.9)	134 (47.2)	687 (60.1)	218 (57.2)	222 (58.3)	247 (64.8)

Notes: Continuous variables presented as means (± standard deviation) or medians (interquartile range) depending on distribution; categorical variables as frequencies, and percentages. Late-, intermediate-, and early-starting groups are based on tertiles of GFR values at the moment of dialysis initiation.

Abbreviations: ACE, angiotensin-converting enzyme; BMI, body mass index; eGFR, estimated, glomerular filtration rate; GFR, glomerular filtration rate; HD, hemodialysis; mGFR, measured glomerular filtration rate.

Figure 3 Kaplan–Meier survival curves for late, intermediate, and early starters.

Notes: mGFR (A, B) and eGFR (C, D), either from dialysis initiation (A, C) or from a GFR value of 20 mL/min/1.73 m² (B, D).
Abbreviations: mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtration rate.

Table 2 Effect of GFR at dialysis initiation on survival and length of lead time

	Crude HR (95% CI)	Adjusted HR (95% CI)a	Length of lead timeb
Data on mGFR
Without correction for lead time
Late starters (<4.3)	Reference	Reference
Intermediate starters (4.3–6.6)	0.86 (0.67–1.1)	1 (0.77–1.28)
Early starters (>6.6)	0.79 (0.61–1.02)	0.8 (0.62–1.03)
With correction for lead time
Late starters	Reference	Reference
Intermediate starters	1.02 (0.8–1.31)	1.23 (0.95–1.58)	6.3
Early starters	1.14 (0.88–1.47)	1.21 (0.93–1.56)	13.9
Data on eGFR
Without correction for lead time
Late starters (<5.7)	Reference	Reference
Intermediate starters (5.7–7.9)	1.21 (0.96–1.53)	1.02 (0.8–1.29)
Early starters (>7.9)	1.55 (1.24–1.94)	1.03 (0.81–1.3)
With correction for lead time
Late starters	Reference	Reference
Intermediate starters	1.33 (1.06–1.69)	1.12 (0.88–1.42)	3.6
Early starters	1.97 (1.58–2.47)	1.33 (1.05–1.68)	9.2

Note:

a Adjusted for age, sex, Khan comorbidity score, primary kidney diseases, and ethnicity;

b length of lead time (months) = Δbaseline GFR/annual GFR slope from PREPARE-1, eg, length of lead time for early versus late starters based on mGFR data = (8.9–2.5)/5.5=13.9 months.

Abbreviations: GFR, glomerular filtration rate; HR, hazard ratio; CI, confidence interval; mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtration rate.

Table 3 Effect of GFR at dialysis initiation on survival and length of lead time

	Crude HR (95% CI)	Adjusted HR (95% CI)a	Length of lead timeb
Data on mGFR
With correction for lead time
Late starters (<4.3)	Reference	Reference
Intermediate starters (4.3–6.6)	0.9 (0.64–1.28)	0.92 (0.65–1.31)	6.8
Early starters (>6.6)	0.9 (0.65–1.26)	0.94 (0.65–1.34)	25.6
Data on eGFR
With correction for lead time
Late starters (<5.7)	Reference	Reference
Intermediate starters (5.7–7.9)	1.35 (1.01–1.8)	1.1 (0.81–1.2)	5.1
Early starters (>7.9)	1.72 (1.29–2.28)	1.1 (0.82–1.48)	14.5

Notes:

a Adjusted for age, sex, Khan comorbidity score, primary kidney diseases, and ethnicity;

b length of lead time (months) = Δbaseline GFR/annual GFR slope from NECOSAD, eg, length of lead time for early versus late starters based on mGFR data = (8.9–2.5)/3=25.6 months.

Abbreviations: GFR, glomerular filtration rate; HR, hazard ratio; CI, confidence interval; mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtration rate; NECOSAD, Netherlands Cooperative on the Adequacy of Dialysis-2.

Table 4 Rates of kidney function decline in PREPARE-1

n	211
Rate of mGFR decline (mL/min/1.73 m^2/year)	−5.5 (±6.4)
mGFR value at dialysis initiation	6.2 (±1.9)
n	336
Rate of eGFR decline (mL/min/1.73 m^2/year)	−7.6 (±8.9)
eGFR value at dialysis initiation	8.3 (±4.1)

Notes: Decline rates shown are means (± standard deviation).

Abbreviations: mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtration rate; PREPARE-1, PREdialysis PAtient REcord-1.

Table 5 Rates of kidney function decline in NECOSAD

		Mean decline (mL/min/1.73 m^2/year)
mGFR	Late starters	−7.4 (±12)
	Intermediate starters	−5.1 (±11.7)
	Early starters	−3 (±12.7)
eGFR	Late starters	−5.6 (±9.4)
	Intermediate starters	−5.4 (±9.4)
	Early starters	−4.8 (±10.5)

Notes: Decline rates shown are means (± standard deviation).

Abbreviations: mGFR, measured glomerular filtration rate; eGFR, estimated GFR; NECOSAD, Netherlands Cooperative on the Adequacy of Dialysis-2.

Table 6 Effect of GFR at dialysis initiation on survival and length of lead time based on literature search

	Crude HR (95% CI)	Adjusted HR (95% CI)a	Length of lead timeb
Data on mGFR
With correction for lead time based on:
Lowest value in literature (−3.2)c
Late starters	Reference	Reference
Intermediate starters	1.14 (0.89–1.47)	1.4 (1.09–1.81)	10.9
Early starters	1.48 (1.15–1.9)	1.61 (1.24–2.09)	23.6
Highest value in literature (−6.6)c
Late starters	Reference	Reference
Intermediate starters	0.99 (0.78–1.28)	1.19 (0.93–1.54)	5.3
Early starters	1.08 (0.84–1.39)	1.14 (0.88–1.47)	11.5
Data on eGFR
With correction for lead time based on:
Lowest value in literature (−4.7)c
Late starters	Reference	Reference
Intermediate starters	1.4 (1.11–1.77)	1.8 (0.93–1.49)	5.9
Early starters	2.25 (1.79–2.81)	1.52 (1.21–1.92)	15.3
Highest value in literature (−12.1)c
Late starters	Reference	Reference
Intermediate starters	1.29 (1.02–1.63)	1.08 (0.85–1.37)	2.3
Early starters	1.81 (1.45–2.27)	1.22 (0.96–1.54)	6

Notes:

a Adjusted for age, sex, Khan comorbidity score, primary kidney diseases, and ethnicity;

b length of lead time (months) = Δbaseline GFR/annual GFR slope;

c annual GFR decline (mL/min/1.73 m²) in the year prior to dialysis initiation.

Abbreviations: GFR, glomerular filtration rate; HR, hazard ratio; CI, confidence interval; mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtration rate.

Table S1 Annual rates of kidney function decline prior to dialysis initiation for late, intermediate, and early starters with available data in PREPARE-1 and NECOSAD

	PREPARE-1		NECOSAD*
	Patients, n	GFR decline (mL/min/1.73 m^2/year)	Patients, n	GFR decline (mL/min/1.73 m^2/year)
mGFR decline	n=211		n=150
Late starters	29	−7.2 (±6.3)	11	−9.6 (±8.5)
Intermediate starters	96	−5.9 (±6.3)	55	−8.1 (±9.9)
Early starters	83	−4.5 (±6.4)	84	−3.6 (±11.3)
eGFR decline	n=336		n=363
Late starters	73	−8.2 (±9.3)	78	−6.4 (±5.9)
Intermediate starters	109	−7.1 (±6)	104	−6.5 (±7.8)
Early starters	154	−7.7 (±10.3)	181	−7.2 (±11.8)

Notes:

* Selection of patients with available data on GFR decline rates prior to dialysis initiation. Decline rates shown are means (± standard deviation).

Abbreviations: GFR, glomerular filtration rate; mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtration rate; PREPARE-1, PREdialysis PAtient REcord-1; NECOSAD, Netherlands Cooperative on the Adequacy of Dialysis-2.

Table S2 Effect of GFR at dialysis initiation on survival and length of lead time

	Adjusted HR (95% CI)a	Adjusted HR (95% CI)b
Data on mGFR
Without correction for lead time
Late starters (<4.3)	Reference	Reference
Intermediate starters (4.3–6.6)	0.97 (0.74–1.25)	0.97 (0.75–1.26)
Early starters (>6.6)	0.76 (0.59–0.99)	0.76 (0.59–0.99)
With correction for lead time
Late starters	Reference	Reference
Intermediate starters	1.21 (0.93–1.57)	0.88 (0.61–1.26)
Early starters	1.16 (0.89–1.51)	0.91 (0.64–1.31)
Data on eGFR
Without correction for lead time
Late starters (<5.7)	Reference	Reference
Intermediate starters (5.7–7.9)	1.02 (0.8–1.3)	1.02 (0.8–1.3)
Early starters (>7.9)	0.99 (0.78–1.25)	0.99 (0.78–1.25)
With correction for lead time
Late starters	Reference	Reference
Intermediate starters	1.13 (0.89–1.43)	1.13 (0.83–1.54)
Early starters	1.28 (1.01–1.62)	1.09 (0.8–1.47)

Notes:

a Adjusted HR for model with mean GFR decline from PREPARE-1^1–3;

b adjusted HR for the model with individual GFR declines from NECOSAD⁴. Adjusted for age, sex, ethnicity, Khan comorbidity score, primary kidney diseases, systolic and diastolic blood pressure, smoking, and antihypertensive use.

Abbreviations: GFR, glomerular filtration rate; HR, hazard ratio; CI, confidence interval; mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtration rate; PREPARE-1, PREdialysis PAtient REcord-1; NECOSAD, Netherlands Cooperative on the Adequacy of Dialysis-2.

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