Beta2-Microglobulin and Alpha1-Microglobulin as Markers of Balkan Endemic Nephropathy, a Worldwide Disease

Figures & data

Table 1.  Characteristics of examined groups

	Balkan nephropathy	Glomerulonephritis	Nephrosclerosis	Controls from non-BEN families	Controls from BENfamilies	p-Value^a
Number	47	36	11	46	30
Age, yrs	68.5 ± 9.6	40.4 ± 11.9	65.8 ± 10.3	63.3 ± 13.9	56.4 ± 13.8	<0.001
Gender (F/M), number	10/37	19/17	2/9	22/24	12/18	<0.05
Systolic BP, mmHg	152 ± 25	138 ± 20	151 ± 15	148 ± 22	147 ± 25	0.066
Diastolic BP, mmHg	89 ± 10	85 ± 15**	92 ± 12	92 ± 11	90 ± 14	<0.05
Hemoglobin, g/L	123 ± 22***	131 ± 20	132 ± 10	134 ± 13	137 ± 17	<0.01
s-Urea, mmol/L	11.4 ± 5.7	7.0 ± 4.2	9.8 ± 3.2***	6.4 ± 2.4	6.0 ± 2.3	<0.001
s-Creatinine, µmol/L	167 ± 123***	115 ± 44***	154 ± 48***	89 ± 23	94 ± 24	<0.001
GFR (MDRD),mL/min/1.73 m^2	50.5 ± 23.1****	76.4 ± 37.1	43.4 ± 12.4****	73.8 ± 16.2	72.5 ± 19.3	<0.001

Notes: Values are means ± SD. BEN, Balkan endemic nephropathy; GFR, glomerular filtration rate.

^aStatistical significance of the differences between the groups calculated by ANOVA and chi-square test as appropriate.

*p < 0.05 in comparison with all other groups;

**p < 0.05 in comparison with controls from non-BEN families;

***p < 0.05 in comparison with both control groups;

****p < 0.05 in comparison with GN and both controls.

Table 2.  Urine excretion of protein, albumin, and low molecular weight proteins

	Balkan nephropathy	Glomerulonephritis	Nephrosclerosis	Control from non-BEN families	Control from BEN families	p-Value^a
Urine protein, mg/mmol creatinine	18.7 (3.0–49.8)	46.8** (13.0–130.1)	4.7 (1.4–11.9)	3.3 (1.7–5.5)	3.2 (1.7–5.5)	<0.001
Urine albumin, mg/mmol creatinine	3.1 (0.7–18.8)	25.3*** (6.0–58.3)	0.4 (0.1–8.5)	0.5 (0.3–1.2)	0.4 (0.2–2.4)	<0.001
Beta2-MG, µg/mmol creatinine	140*** (22.3–1950.4)	8.0 (3.1–14.6)	13.4 (1.5–33.2)	8.3 (2.4–29.1)	7.0 (5.1–18.7)	<0.001
Alpha1-MG, mg/mmol creatinine	1.8**** (0.9–4.4)	0.8 (0.4–1.3)	0.7 (0.4–1.7)	0.7 (0.5–1.0)	0.5 (0.3–0.7)	<0.001

Notes: Values are expressed as median/interquartile ranges (lower quartile–upper quartile). BEN, Balkan endemic nephropathy.

^aStatistical significance of the differences between the groups calculated by ANOVA.

*p < 0.05 in comparison with both control groups;

**p < 0.05 in comparison with nephrosclerosis and both control groups;

***p < 0.05 in comparison with all other groups;

****p < 0.05 in comparison with GN and both controls.

Figure 1. Individual values of urine albumin in patients with Balkan endemic nephropathy (BEN), glomerulonephritis (GN), nephrosclerosis (NS), healthy controls from non-BEN families (C-nonBEN), and healthy controls from BEN families (C-BEN).

Figure 2. Individual values of urine beta2-microglobulin in patients with Balkan endemic nephropathy (BEN), glomerulonephritis (GN), nephrosclerosis (NS), healthy controls from non-BEN families (C-nonBEN), and healthy controls from BEN families (C-BEN).

Figure 3. Individual values of urine alpha1-microglobulin in patients with Balkan endemic nephropathy (BEN), glomerulonephritis (GN), nephrosclerosis (NS), healthy controls from non-BEN families (C-nonBEN), and healthy controls from BEN families (C-BEN).

Table 3.  Areas under the curve and 95% confidence interval for four urine markers used in the differentiation of Balkan endemic nephropathy, glomerulonephritis, and nephrosclerosis from healthy controls from nonendemic families

	Balkan endemic nephropathy	Glomerulonephritis	Nephrosclerosis
Urine protein	0.777 (0.671–0.862)	0.854(0.750–0.926),**	0.595 (0.442–0.735) ***
Urine albumin	0.740 (0.631–0.831)	0.872(0.771–0.939),**	0.500 (0.351–0.649)
Beta2-MG	0.828 (0.728–0.903)****	0.485(0.364–0.607)	0.578 (0.426–0.721)****
Alpha1-MG	0.782 (0.677–0.866)	0.502(0.380–0.623)	0.562 (0.410–0.706)****

Notes:

****p < 0.05 versus albumin;

*p < 0.001 versus alpha 1-MG;

**p < 0.001 versus beta 2-MG;

***p < 0.01 versus albumin of the same patient group.

Figure 4. ROC analysis for four examined urinary markers in differentiating BEN from healthy controls (left pannel), and GN from healthy controls (right pannel).

Table 4.  The results of ROC curves analysis of four urinary markers in healthy persons, patients with glomerulonephritis, and nephrosclerosis in comparison with BEN patients

Marker	Healthy persons versus BEN					Glomerulonephritis versus BEN					Nephrosclerosis versus BEN
	Cutoff	Sn	Sp	Diff. AUCs	p-Value	Cutoff	Sn	Sp	Diff. AUCs	p-Value	Cutoff	Sn	Sp	Diff. AUCs	p-Value
Urine protein, mg/mmol creatinine	>8.02	65.9	92.1	0.226	<0.05	>8.02	80	92	0.110	>0.05	>3.38	70	55	0.193	>0.05
Urine albumin, mg/mmol creatinine	>1.23	65.2	80.4	0.242	<0.05	>5.02	75	96	0.129	<0.05	>3.13	36	89	0.270	>0.05
Beta2-MG, µg/mmol creatinine	>44.66	72.3	84.4	0.361	<0.001	<17.2	86	38	0.325	<0.001	>22.47	46	73	0.318	<0.01
Alpha1-MG, mg/mmol creatinine	>1.12	70.2	82.6	0.142	>0.05	<0.43	36	83	0.298	<0.01	>1.65	27	89	0.344	<0.05

Note: BEN, Balkan endemic nephropathy; Sn, sensitivity; Sp, specificity; Diff. AUCs, difference in areas under the curve.