Endogenous markers for kidney function in children: a review

Figures & data

Figure 1. Development of GFR with age. Presentation of 5th and 95th percentile of GFR measured by inulin clearance in healthy children. Data derived from Brodehl et al. [4].

Figure 2. Factors influencing serum concentrations of endogenous eGFR markers.

Table 1. Characteristics of endogenous marker for kidney function.

Marker	Molecular mass	Iso-electric point	Derived from	Volume of distribution	Interactions
Creatinine	113 Da	8.74	Muscle	Total body fluid	Muscle mass, cooked meat, fish, medication
Urea	60 Da		Protein catabolism	Total body fluid	Catabolic state, hydration, internalbleeding, GCS
Beta-2 microglobulin	11 800 Da	5.4–5.7	All nucleated cells	Extra-cellular fluid	Viral infections, malignancies, GCS
Cystatin C	13 300 Da	9.30	All nucleated cells	Extra-cellular fluid	Thyroid dysfunction, GCS
Beta-trace protein	23 000 Da	5.8–6.7	Cerebrospinal fluid	Extra-cellular fluid	GCS

GCS: glucocorticoid therapy.

Figure 3. Serum creatinine versus GFR for different rates of creatinine production and tubular secretion. By courtesy of Professor Jack F. M. Wetzels, Nijmegen (modified).

Figure 4. Model of changes in serum creatinine. Acute decrease in GFR by 25, 50 or 75% at 24 h. (a) baseline GFR 100 mL/min/1.73 m², (b) baseline GFR 50 mL/min/1.73 m^2. From Slort et al. [30], used with permission.

Figure 5. Serum creatinine versus age. Data from Bökenkamp et al. [43], used with permission.

Figure 6. Serum cystatin C versus age. Grey area indicates reference range (DAKO PETIA, calibration 1998) First published by Data from Bökenkamp et al. [43], used with permission.

Figure 7. Relationship between true GFR, measured GFR, marker concentration and estimated GFR.

Table 2. eGFR Equations based on different endogenous markers.

Study	Equation	Assay	Population	Gold standard used	GFR (mL/min/1.73 m^2)	P30 accuracy
Creatinine based
Schwartz 2009 [203]	eGFR =0.413 × height (cm)/sCr (mg/dL)	Enzymatic	349 children; 1–16 years; mild to moderate CKD; 20% GN, 73% non-GN, 7% other	Iohexol plasma clearance	41.3	79.4%
Hari 2012 [204]	eGFR =0.42 × height (cm)/sCr (mg/dL)	Jaffe	197 children; 2–18 years; CKD stages I–IV; 83 % urological disease, 10 % GN	^99mTc-DTPA plasma clearance	80.5	71.4%
Pottel 2012 [193]	eGFR =107.3/(sCr/Q) Q = age- or height-based normal value	Enzymatic below age 5 years, Jaffe above	353 children; 1.6–14 years; healthy	^51Cr-EDTA plasma clearance	104	72.8%
Schwartz 2012 [117]	eGFR =0.423 × [height (cm)/sCr (mg/dL)]^0.79	Enzymatic	643 children; 1–16 years	Iohexol plasma clearance	43.3	80.4%
De Souza 2012 [208]	eGFR = k × height (cm) /sCr (mg/dL), where k = 0.325 for <13 years, 0.365 for boys >13 years and 0.325 for girls >13 years	Jaffe	360 children; renal transplant, other transplants, glomerular disease, CKD	Inulin urinary clearance	86.0	91%
Nagai 2013 [205]	eGFR =0.35 × height (cm)/sCr (mg/dL)	Enzymatic	174 children; 2–11 years; mostly urological disease	Inulin urinary clearance	65.4	n.a.
Hoste 2014 [194]	eGFR =107.3/(sCr/Q) Q = age- or height-based normal value	Enzymatic	15 978 healthy children from 0.1 to 20 years. Validation in 418 children	Inulin urinary clearance (validation)	n.a.	91.2%
Uemura 2014 [182]	eGFR =110.2 × sCrref/sCr (mg/dL) + 2.93 sCrref based on height	Enzymatic	131 children; 1 month–18 years mostly urological disease	Inulin urinary clearance	58.8–74.6	82%
Pottel 2016 [196]	eGFR =107.3/(sCr/Q) Q = age- or height-based normal value	Enzymatic	Validation in 735 children and 1764 adults, healthy individuals	Iohexol plasma clearance, inulin urinary clearance, iothalamate plasma clearance	94.5	87.5%
Millisor 2017 [189]	eGFR =0.33 × (height (cm) /sCr (mg/dL))	Enzymatic	299 children with malignancy	^99mTc-DTPA plasma clearance	105 patients <60 194 patients >60	76.33%
Cystatin C based
Schwartz 2012 [117]	eGFR =40.6 × (1.8/sCys (mg/L/1.17)^0.93	PENIA	643 children; 1–16 years	Iohexol plasma clearance	43.3	82.6%
Uemura 2014 [206]	eGFR =104.1 × 1/ sCys (mg/L) – 7.80	PETIA	135 children; 1 month–18 years, mostly urological disease	Inulin urinary clearance	66.3	84%
Grubb 2014 [216] (CAPA)	eGFR= 130 × sCys (mg/L)^−1.069 × age (years)^−0.117 – 7	Six different PENIA/PETIA assays	2708 adults and 456 children	Iohexol plasma clearance, inulin urinary clearance, inulin plasma clearance	Adults 53–54 Children 103	80.1%
Berg 2015 [209]	eGFR =91 × sCys (mg/L)^−1.213	Mostly PENIA, some PETIA	220 children; 4–18 years; various renal diseases (Tx, NS, GN, DM)	Inulin urinary clearance	84	86%
Pottel 2017 [207]	eGFR =107.3 × sCys (mg/L)/0.82	Different PENIA/PETIA	5764 adults and 368 children	Various	n.a.	86.1%
B2M based
Ikezumi 2015 [183]	eGFR =149 × (1/B2M (mg/L)) + 9.15	PETIA	174 children; 1 month–18 years; mostly urological disease	Inulin urinary clearance	71.8	n.a.
BTP based
Abbink 2008 [217]	eGFR = −35.20 + 122.74 × BTP (mg/L)^−0.5	PENIA	85 children, mean age 9.7 years, 35 oncology, 50 nephrology patients	Inulin plasma clearance	90.2	65.6–81.6%
Benlamri 2010 [188]	eGFR =79.8 × [1/BTP (mg/L])^0.9515	PENIA	474 children; 0.21–18.9 years Various renal pathology	^99mTc-DTPA plasma clearance	105.5	76.8%
Combined
Schwartz 2012 [117] (CKiD3)	eGFR =39.1 × [height (cm)/sCr (mg/dL)]^0.516 × [1.8/sCys (mg/L )]^0.94 × [30/BUN (mg/dL)]^0.169 × 1.099^1 if male × [height (cm)/1.4]^0.188	Enzymatic and PETIA	643 children; 1–16 years	Iohexol plasma clearance	41.3	91.0%
Chehade 2014 [210]	For boys: eGFR =0.42 × (height/sCr) – 0.04 × (height/sCr)^2 – 14.5 × sCys +0.69 × age +21.88 For girls: eGFR= 0.42 × (height/sCr) – 0.04 × (height/sCr)^2 – 14.5 × sCys +0.69 × age +18.25	Jaffe and PENIA	243 children; 2–18.5 years. Mostly obstructive nephropathy or single kidney	Inulin urinary clearance	85	97%
Witzel 2015 [135]	For boys: eGFR =666.8/BTP (mg/L)^0.461/sCr (mmol/L)^0.679) × 10^0.00259× height (cm)For girls: eGFR =591.6/BTP(mg/L)^0.433/sCr (mmol/L)^0.661 × 10^0.00256× height (cm)	Enzymatic and PENIA	504 children; 2–18 years, various renal pathology	^99mTc-DTPA plasma clearance	110	80.2–88.6%

eGFR: estimated glomerular filtration rate; sCr: serum creatinine concentration; sCys: serum cystatin C concentration; B2M: serum beta-2 microglobulin concentration; BTP: serum beta-trace protein concentration; PENIA: particle enhanced nephelometric immune assay; PETIA: particle enhanced turbidimetric immune assay; CKD: chronic kidney disease; GN: glomerulonephritis; Tx: transplanted; NS: nephrotic syndrome; DM: diabetes mellitus.

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