Comparison of three spot proteinuria measurements for pediatric nephrotic syndrome: based on the International pediatric Nephrology Association 2022 Guidelines

Figures & data

Table 1. Definitions related to nephrotic syndrome in children based on IPNA 2022 Guidelines [2].

Term	Definition
Nephrotic syndrome	Nephrotic-range proteinuria (UPCR ≥ 200 mg/mmol (2 mg/mg), or 24-h UP ≥ 1000 mg/m^2 per day corresponding to urine dipstick 3+ (300–1000 mg/dL) or 4+ (≥ 1000 mg/dL)) and either hypoalbuminemia (serum albumin < 30 g/L) or edema when serum albumin is not available
Steroid-sensitive nephrotic syndrome	Complete remission within 4 weeks of prednisolone at standard dose (60 mg/m^2/day or 2 mg/kg/day, maximum 60 mg/day)
Steroid-resistant nephrotic syndrome	Lack of complete remission within 4 weeks of treatment with prednisolone at standard dose
Complete remission	UPCR ≤ 20 mg/mmol (0.2 mg/mg) or 24-h UP < 100 mg/m^2 per day, respectively, or negative or trace dipstick on three or more consecutive days
Partial remission	UPCR > 20 but < 200 mg/mmol (> 0.2 mg/mg but < 2 mg/mg) and serum albumin ≥ 30 g/L
Relapse (no remission)	Urine dipstick ≥ 3+ (≥ 300 mg/dl) or UPCR ≥ 200 mg/mmol (≥ 2 mg/mg) on 3 consecutive days in a child who had previously achieved complete remission

UPCR: urinary protein creatinine ratio; 24-h UP: 24-h urine protein.

Figure 1. Study workflow. Created with BioRender.com. eGFR: estimated glomerular filtration rate; IPNA: International Pediatric Nephrology Association; UPCR: urinary protein creatinine ratio; 24-h UP: 24-hour urine protein

Table 2. Nephrotic syndrome patient characteristics.

Characteristics	Value
Male (n) (%)	58 (63.04)
Age, years (median (IQR))	10.04 (6.54–12.96)
Estimated glomerular filtration rate (mL/min per 1.73 m^2)	109.65 (92.03–132.57)
24-h UP, mg/m^2/day (median (IQR))	141.67 (82.99–796.59)
UPCR, mg/mg (median (IQR))	0.53 (0.22–2.46)
Urine creatinine, mg/dL (median (IQR))	70.74 (31.97–134.99)
Urine specific gravity (median (IQR))	1.020 (1.010–1.025)
<1.005 (n) (%)	8 (8.7)
1.005–1.030 (n) (%)	81 (88.04)
>1.030 (n) (%)	3 (3.26)
Nutritional status* (n) (%)
Underweight (BMI-for-age < 5^th percentile)	9 (9.78)
Normal (BMI-for-age ≥ 5^th and < 85^th percentile)	61 (66.3)
Overweight (BMI-for-age ≥ 85^th and < 95^th percentile)	11 (11.96)
Obese (BMI-for-age ≥ 95^th percentile)	11 (11.96)
Nephrotic syndrome diagnosis (n) (%)
Initial diagnosis	2 (2.17)
Primary steroid-sensitive	2 (2.17)
Steroid-dependent	13 (14.13)
Steroid-resistant	75 (81.52)
Proteinuria categories based on 24-h UP/m^2/day (%)
No remission	21 (22.83)
Partial remission	38 (41.3)
Complete remission	33 (35.87)
Proteinuria categories based on UPCR (mg/mg)
No remission	26 (28.26)
Partial remission	49 (53.26)
Complete remission	17 (18.48)
Proteinuria categories based on automated urinary dipstick (n) (%)
No remission	19 (20.65)
Partial remission	24 (26.09)
Complete remission	49 (53.26)
Proteinuria categories based on manual urinary dipstick (n) (%)
No remission	8 (8.7)
Partial remission	32 (34.78)
Complete remission	52 (56.52)

*Centers for Disease Control and Prevention (CDC) classification of nutritional status of children and adolescents, 2 to 20 years.

BMI: body mass index; IQR: interquartile range; UPCR: urinary protein creatinine ratio; 24-h UP: 24-h urine protein.

Table 3. Correlation coefficients between morning spot proteinuria measurements and 24-h urine protein.

Proteinuria Measurement	Spearman correlation (r) (95%CI)	p-value
UPCR	0.83 (0.73–0.91)	< 0.001
Automated urinary dipstick	0.79 (0.72–0.86)	< 0.001
Manual urinary dipstick	0.78 (0.7–0.87)	< 0.001

CI: confidence interval; UPCR: urinary protein creatinine ratio.

Table 4. Sensitivity, specificity, and predictive values of morning spot proteinuria assessments to identify no remission/relapse based on IPNA 2022 Guidelines.

Proteinuria measurement	Sensitivity (%)	Specificity (%)	Predictive value
			Positive (%)	Negative (%)
UPCR	95.24	91.55	76.92	98.48
Automated urinary dipstick	52.38	88.73	57.89	86.3
Manual urinary dipstick	33.33	98.59	87.5	83.3

IPNA: International Pediatric Nephrology Association; UPCR: urinary protein creatinine ratio.

Power analysis of UPCR, automated, and manual dipstick sensitivity was 99%, 47.6%, and 51.6%, respectively.

Power analysis of UPCR, automated, and manual dipstick specificity was 92.5%, 85.1%, and 100%, respectively.

Table 5. Sensitivity, specificity, and predictive values of morning spot proteinuria assessments to identify complete remission based on IPNA 2022 Guidelines.

Proteinuria Measurement	Sensitivity (%)	Specificity (%)	Predictive value
			Positive (%)	Negative (%)
UPCR	94.92	42.42	74.67	82.35
Automated urinary dipstick	64.41	93.94	95	59.62
Manual urinary dipstick	67.8	90.91	93.02	61.22

IPNA: International Pediatric Nephrology Association; UPCR: urinary protein creatinine ratio.

Power analysis of UPCR, automated, and manual dipstick sensitivity to identify complete remission was 99%, 51.6%, and 55.6%, respectively.

Power analysis of UPCR, automated, and manual dipstick specificity was 47.6%, 97.9%, and 91%, respectively.

Figure 2. The receiver operator characteristics curve showed that the optimal cutoff urinary protein creatinine ratio for no remission/relapse was 2.08 mg/mg with an AUC value of 0.93. AUC: area under the curve; CI: confidence interval; ROC: receiver operator characteristics; UPCR: urinary protein creatinine ratio

Figure 3. The receiver operator characteristics curve showed the optimal cutoff of urinary protein creatinine ratio for complete remission was 0.44 mg/mg with an AUC value of 0.83. AUC: area under the curve; CI: confidence interval; ROC: receiver operator characteristics; UPCR: urinary protein creatinine ratio

Table 6. Sensitivity, specificity, and predictive values of UPCR cutoff based on IPNA 2022 Guidelines and the value in our study for diagnosing complete remission.

UPCR Cutoff (mg/mg)	Sensitivity (%)	Specificity (%)	Predictive value		Youden Index
			Positive (%)	Negative (%)
0.2	94.92	42.42	74.67	82.35	0.37
0.44	77.97	87.88	92	69.05	0.66

IPNA: International Pediatric Nephrology Association; UPCR: urinary protein creatinine ratio.

Figure 4. The receiver operator characteristics curve showed that the manual dipstick had higher AUC value of 0.93 compared to the automated dipstick for identifying no remission/relapse, k = 0.53 (p < 0.001). AUC: area under the curve; CI: confidence interval; ROC: receiver operator characteristics

Figure 5. The receiver operator characteristics curve showed that the automated dipstick had higher AUC value of 0.85 compared to the manual dipstick for identifying complete remission, k = 0.53 (p < 0.001). AUC: area under the curve; CI: confidence interval; ROC: receiver operator characteristics

Table 7. The cutoff points of automated and manual dipstick tests with the best combination of sensitivity and specificity in predicting complete remission and no remission/relapse using IPNA 2022 Guidelines as proteinuria gold standard.

Diagnosis	Dipstick test method	Cutoff based on the highest Youden Index	Sensitivity (%)	Specificity (%)	Predictive value
					Positive (%)	Negative (%)
Complete remission	Automated	1+	62.71	100	100	60
	Manual	Trace	64.41	93.94	95	59.62
No remission/ relapse	Automated	2+	95.24	76.06	54.05	98.18
	Manual	1+	100	73.24	52.5	100

k = 0.53 (p < 0.001).

Table 8. Steroid-resistant nephrotic syndrome patient characteristics.

Characteristics	Value
Male (n) (%)	49 (65.33)
Age, years (median (IQR))	10.58 (7.83–13.42)
eGFR (mL/min per 1.73 m2)	111.51 (94.4–132.16)
Kidney biopsy (n) (%)	33 (44)
Histology
Focal segmental glomerulosclerosis	16 (48.49)
Minimal change disease	5 (15.15)
Mesangial proliferative glomerulonephritis	8 (24.24)
Global/focal global glomerulosclerosis	4 (12.12)
Hematuria (n) (%)	19 (25.33)
24-h UP, mg/m^2/day (median (IQR))	143.84 (83.84–1079.59)
UPCR, mg/mg (median (IQR))	0.49 (0.22–2.76)
Urine creatinine, mg/dL (median (IQR))	87.82 (40–156.49)
Urine specific gravity (median (IQR))	1.02 (1.015–1.02)
<1.005 (n) (%)	4 (5.33)
1.005–1.030 (n) (%)	68 (90.67)
> 1.030 (n) (%)	3 (4)
Proteinuria categories based on 24-h UP/m^2/day (%)
No remission	21 (28)
Partial remission	28 (37.33)
Complete remission	36 (34.67)
Proteinuria categories based on UPCR (mg/mg)
No remission	23 (30.67)
Partial remission	39 (52)
Complete remission	13 (17.33)
Proteinuria categories based on automated urinary dipstick (n) (%)
No remission	17 (22.67)
Partial remission	19 (25.33)
Complete remission	39 (52)
Proteinuria categories based on manual urinary dipstick (n) (%)
No remission	8 (10.67)
Partial remission	28 (37.33)
Complete remission	39 (52)

eGFR: estimated glomerular filtration rate; IQR: interquartile range; UPCR: urinary protein creatinine ratio; 24-h UP: 24-h urine protein.

Table 9. Sensitivity, specificity, and predictive values of morning spot proteinuria assessments to identify relapse and complete remission based on IPNA 2022 Guidelines.

Proteinuria measurement	Sensitivity (%)	Specificity (%)	Predictive value
			Positive (%)	Negative (%)
Relapse diagnosis
UPCR	95.24	94.44	86.96	98.08
Automated urinary dipstick	52.38	88.89	64.71	82.76
Manual urinary dipstick	33.33	98.15	87.5	79.1
Remission diagnosis
UPCR	93.88	38.46	74.19	76.92
Automated urinary dipstick	69.39	92.31	94.44	61.54
Manual urinary dipstick	69.39	92.31	94.44	61.54

IPNA: International Pediatric Nephrology Association; UPCR: urinary protein creatinine ratio.

Trautmann A, Schnaidt S, Lipska-Ziętkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28(10):3055–11. doi: 10.1681/ASN.2016101121.

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Data availability statement

All data analyzed or generated are included in this article and the Supplementary Materials. Further inquiries regarding data can be directed to the corresponding author.