Confirming the Utility of Four Kidney Biomarker Tests in a Longitudinal Follow-Up Study

Figures & data

Table 1. Distribution of biomarkers among healthya participants aged 8 through 55 years by sex and selection criteriab for inclusion in the follow-up study

Biomarkerc	Sex	N	Median	5–95th percentile	Selection criteria and definition of “elevated level”b
AAP (U/g)	M	589	4.19	1.49–10.16	11
	F	538	3.74	1.36–7.53	8
NAG (U/g)	M	590	0.64	0.12–1.75	1.8
	F	537	0.72	0.18–1.86	1.9
ALB (mg/g)	M	590	5.0	2.4–21.1	20
	F	539	6.7	3.2–40.9	20
RBP (mg/g)	M	589	0.047	0.011–0.134	0.14
	F	539	0.052	0.011–0.164	0.17

Abbreviations: AAP, alanine aminopeptidase; ALB, albumin; NAG, N-acetyl-β-d-glucosaminidase; RBP, retinol-binding protein.

^aParticipants with urine creatinine levels between 30 and 400 mg/L and who in the original studies self-reported that they (a) never had diabetes, heart disease, hypertension, gout, kidney disease, cancer, or chemotherapy; (b) did not have any urinary tract disease; and (c) were not pregnant.

^bParticipants from the original studies with a baseline biomarker value above the selection criteria were selected for this study and their participation was sought. This same value was used as the definition of “elevated” for statistical analyses.

^cBiomarkers were adjusted for urinary dilution using the ratio to creatinine. All values are given per gram of urine creatinine.

Figure 1. Selection criteria and participation in the follow-up study.

Table 2. Comparison of baseline and follow-up biomarker values among participants 8–19 years of age, by age at follow-up.a

Baseline test value	Age <20 years at follow-up new test value		Total	Age ≥20 years at follow-up new test value		Total
	Elevated	Not elevated		Elevated	Not elevated
Any of the four
Elevated	21 (48%)	23 (52%)	44	1b (8%)	12 (92%)	13
Not elevated	5 (14%)	32 (86%)	37	0 (0%)	19 (100%)	19
AAP
Elevated	1 (11%)	8 (89%)	9	0	1	1
Not elevated	3 (8%)	33 (92%)	36	0	18	18
ALB
Elevated	13 (41%)	19 (59%)	32	0	11	11
Not elevated	2 (5%)	35 (95%)	37	0	19	19
NAG
Elevated	1 (11%)	8 (89%)	9	0	1	1
Not elevated	2 (5%)	35 (95%)	37	0	18	18
RBP
Elevated	3 (27%)	8 (73%)	11	0	3	3
Not elevated	2 (5%)	35 (95%)	37	0	19	19

Abbreviations: AAP, alanine aminopeptidase; ALB, albumin; NAG, N-acetyl-β-d-glucosaminidase; RBP, retinol-binding protein.

^aExcludes participants with an elevated serum creatinine or self-reported kidney disease at baseline.

^bThe one new elevation was a newly elevated NAG among a participant with a baseline elevated albumin. At follow-up, the albumin was normal.

Table 3. Comparison of baseline and follow-up biomarker values among participants 20–75 years of age, by baseline health status.a

Baseline test value	Diabetes at baseline				Other disease at baselineb				No disease at baselinec
	New test value				New test value				New test value
	Elevated	Not elevated	Total	p-Valued	Elevated	Not elevated	Total	p-Valued	Elevated	Not elevated	Total	p-Valued
Any of the four
Elevated	10 (91%)	1 (9%)	11	0.180	30 (60%)	20 (40%)	50	0.074	26 (46%)	30 (54%)	56	0.039
Not elevated	4 (57%)	3 (43%)	7	—	33 (38%)	55 (63%)	88	—	16 (26%)	46 (74%)	62	—
AAP
Elevated	2 (40%)	3 (60%)	5	0.317	11 (69%)	5 (31%)	16	0.011	6 (30%)	14 (70%)	20	0.695
Not elevated	1 (14%)	6 (86%)	7	—	17 (20%)	70 (80%)	87	—	12 (20%)	48 (80%)	60	—
ALB
Elevated	5 (71%)	2 (29%)	7	1.000	4 (44%)	5 (56%)	9	0.090	7 (64%)	4 (36%)	11	0.366
Not elevated	2 (29%)	5 (71%)	7	—	12 (14%)	75 (86%)	87	—	7 (11%)	55 (89%)	62	—
NAG
Elevated	6 (60%)	4 (40%)	10	0.414	19 (58%)	14 (42%)	33	0.847	5 (22%)	18 (78%)	23	0.007
Not elevated	2 (29%)	5 (71%)	7	—	13 (15%)	73 (85%)	86	—	5 (8%)	57 (92%)	62	—
RBP
Elevated	2 (40%)	3 (60%)	5	0.317	3 (23%)	10 (77%)	13	0.197	2 (13%)	13 (87%)	15	0.005
Not elevated	1 (14%)	6 (86%)	7	—	5 (6%)	82 (94%)	87	—	2(3%)	60 (97%)	62	—

Abbreviations: AAP, alanine aminopeptidase; ALB, albumin; NAG, N-acetyl-β-d-glucosaminidase; RBP, retinol-binding protein.

^aExcludes participants with an elevated serum creatinine or self-reported kidney disease at baseline.

^bIncludes self-reported hypertension, heart disease, gout, and urinary tract disease.

^cThese persons reported not ever having kidney disease, diabetes, hypertension, heart disease, gout, and urinary tract disease. Other health conditions might have been present.

^dMcNemar's test.

Table 4. Risk of having elevated serum creatinine, low creatinine clearance, and elevated serum cystatin C values at follow-up, by baseline biomarker status among participantsa 56–75 years of age

	High serum creatinine		Low creatinine clearance		High serum cystatin C
Baseline biomarker value	No. with high serum creatinine (total)	Risk ratiob	No. with creatinine clearance <63 mL (total)	Risk ratio	No. with elevated cystatin C (>1.5 mg.dL) (total)	Risk ratio
Any of the four biomarkers elevated	4 of 69 (6%)	NC, p = 0.030	13 of 63 (21%)	2.5 (1.2–5.2), p = 0.049	6 of 42 (14%)	8.6 (1.5–49.1), p = 0.019
Elevated ALB	2 of 16 (13%)	NC, p = 0.020	5 of 14 (36%)	4.3 (1.9–9.9), p = 0.013	4 of 10 (40%)	24.0 (4.2–138.3), p = 0.001
Elevated AAP	3 of 29 (10%)	NC, p = 0.012	4 of 26 (15%)	1.8 (0.7–4.8), p = 0.285	2 of 15 (13%)	8.0 (1.1–56.7), p = 0.100
Elevated NAG	5 of 45 (11%)	NC, p = 0.003	14 of 43 (33%)	3.6 (1.8–7.4), p = 0.003	6 of 32 (19%)	11.3 (2.0–64.1), p = 0.007
Elevated RBP	1 of 14 (7%)	NC, p = 0.128	2 of 13 (15%)	1.8 (.5–6.3), p = 0.346	3 of 10 (30%)	18.0 (2.9–110.5), p = 0.008
None elevated	0 of 95 (0%)	Reference	8 of 85 (9%)	Reference	1 of 60 (2%)	Reference

Abbreviations: AAP, alanine aminopeptidase; ALB, albumin; NAG, N-acetyl-β-d-glucosaminidase; NC, cannot be computed; RBP, retinol-binding protein.

^aExcludes participants with self-reported kidney disease at baseline or elevated baseline serum creatinine. Sample sizes vary due to missing data.

^b90% confidence interval (logit); Fisher's exact 2-tailed p-value.

Table 5. Risk of having elevated serum creatinine values at follow-up, by baseline biomarker status and baseline health status, among participantsa 20–75 years of age

	Diabetes		Other diseaseb		No diseasec
Baseline biomarker value	No. with high serum creatinine (total)	Risk ratiod	No. with high serum creatinine (total)	Risk ratio	No. with elevated high serum creatinine (total)	Risk ratio
Any of the four biomarkers elevated	2 of 13 (15%)	NC, p = 0.505	2 of 62 (3%)	NC, p = 0.149	1 of 67 (1%)	1.1 (0.1–11.1), p = 1.000
Elevated ALB	2 of 7 (29%)	NC, p = 0.200	0 of 12 (0%)	No difference	0 of 13 (0%)	0, p = 1.00
Elevated AAP	1 of 6 (17%)	NC, p = 0.429	1 of 22 (5%)	NC, p = 0.192	1 of 24 (4%)	3.0 (0.3–29.4), p = 0.443
Elevated NAG	2 of 11 (18%)	NC, p = 0.485	2 of 42 (2%)	NC, p = 0.090	1 of 31 (3%)	2.4 (0.2–23.8), p = 0.505
Elevated RBP	1 of 4 (25%)	NC, p = 0.333	1 of 12 (8%)	NC, p = 0.109	0 of 15 (0%)	0, p = 1.00
None elevated	0 of 8 (0%)	Reference	0 of 98 (0%)	Reference	1 of 74 (1%)	Reference

Abbreviations: AAP, alanine aminopeptidase; ALB, albumin; NAG, N-acetyl-β-d-glucosaminidase; NC, cannot be computed; RBP, retinol-binding protein.

^aExcludes participants with self-reported kidney disease at baseline or elevated baseline serum creatinine.

^bIncludes self-reported hypertension, heart disease, gout, and urinary tract disease.

^cThese persons reported not ever having kidney disease, diabetes, hypertension, heart disease, gout, and urinary tract disease. Other health conditions might have been present.

^d90% confidence interval (logit); Fisher's exact 2-tailed p-value.

Table 6. Risk of having a low creatinine clearance value (<63 mL/min) at follow-up among participantsa 20–75 years of age, by baseline health status

	Diabetes		Other diseaseb		No diseasec
Baseline biomarker value	No. with low creatinine clearance (total)	Risk ratiod	No. with low creatinine clearance (total)	Risk ratio	No. with low creatinine clearance (total)	Risk ratio
Any of the biomarkers	4 of 14 (29%)	NC, p = 0.254	11 of 54 (20%)	1.9 (1.0–3.8), p = 0.138	4 of 57 (7%)	4.4 (0.7–26.7), p = 0.192
ALB	4 of 9 (44%)	NC, p = 0.082	2 of 8 (25%)	2.4 (0.8–7.3), p = 0.209	0 of 8 (0%)	0, p = 1.00
AAP	3 of 7 (43%)	NC, p = 0.077	2 of 18 (11%)	1.0 (0.3–3.5), p = 1.00	1 of 21 (5%)	3.0 (0.3–29.1), p = 0.444
NAG	4 of 12 (33%)	NC, p = 0.117	9 of 37 (24%)	2.6 (1.2–5.3), p = 0.033	4 of 29 (14%)	8.6 (1.4–51.8), p = 0.034
RBP	3 of 6 (50%)	NC, p = 0.055	1 of 10 (10%)	1.05 (0.2–5.5), p = 1.00	0 of 14 (0%)	0, p = 1.00
None	0 of 8 (0%)	Reference	9 of 85 (11%)	Reference	1 of 62 (2%)	Reference

Abbreviations: AAP, alanine aminopeptidase; ALB, albumin; NAG, N-acetyl-β-d-glucosaminidase; NC, cannot be computed; RBP, retinol-binding protein.

Summary, elevated NAG and elevated albumin were the most predictive of having a lower creatinine clearance at follow up than the other two biomarkers.

^aExcludes participants with self-reported kidney disease at baseline, elevated baseline serum creatinine, or problems with urine collection.

^bIncludes self-reported hypertension, heart disease, gout, and urinary tract disease.

^cThese persons reported not ever having kidney disease, diabetes, hypertension, heart disease, gout, and urinary tract disease. Other health conditions might have been present.

^d90% confidence interval from logit estimator; Fisher's exact 2-tailed p-value.

Table 7. Risk of having an elevated serum cystatin C value (>1.5 mg/dL) at follow-up among participants 20–75 years of age, by baseline health status

	Diabetes		Other disease		No disease
Baseline biomarker value	No. with low elevated cystatin (total)	Risk ratioc	No. with low elevated cystatin (total)	Risk ratioc	No. with low elevated cystatin (total)	Risk ratioc
Any	2 of 10 (20%)	NC, p = 0.500	5 of 38 (13%)	8.2 (14–47.9), p = 0.028	2 of 49 (4%)	NC, p = 0.228
ALB	2 of 6 (33%)	NC, p = 0.455	2 of 9 (22%)	13.8 (2.0–94.7), p = 0.041	0 of 10 (0%)	NC, no difference
AAP	1 of 5 (20%)	NC, p = 0.455	2 of 13 (15%)	9.5 (1.4–67.1), p = 0.076	1 of 20 (10%)	NC, p = 0.274
NAG	2 of 9 (22%)	NC, p = 0.486	5 of 28 (18%)	11.1 (1.9–64.5), p = 0.010	2 of 24 (8%)	NC, p = 0.094
RBP	2 of 5 (40%)	NC, p = 0.182	1 of 8 (13%)	7.8 (0.8–73.0), p = 0.217	1 of 9 (11%)	NC, p = 0.145
None	0 of 6 (0%)	Reference	1 of 62 (2%)	Reference	0 of 53 (0%)	Reference

Abbreviations: AAP, alanine aminopeptidase; ALB, albumin; NAG, N-acetyl-β-d-glucosaminidase; NC, cannot be computed; RBP, retinol-binding protein.

^a90% Confidence intervals from logit estimator; Fisher's exact 2-tailed p-value.

^aIncludes self-reported hypertension, heart disease, gout, and urinary tract disease.

^bThese persons reported not ever having kidney disease, diabetes, hypertension, heart disease, gout, and urinary tract disease. Other health conditions might have been present.

^c90% Confidence intervals (logit); Fisher's exact 2-tailed p-value.